1. health and fitness
2. disease

TOXICOLOGICAL SCIENCES 110(1), 4–30 (2009)
doi:10.1093/toxsci/kfp097
Advance Access publication May 4, 2009
REVIEW
Chiral Toxicology: It’s the Same Thing. . .Only Different
Silas W. Smith*,†,1
*New York University School of Medicine, New York, New York 10016; and †New York City Poison Control Center, New York, New York 10016
Received February 18, 2009; accepted April 29, 2009
Chiral substances possess a unique architecture such that,
despite sharing identical molecular formulas, atom-to-atom linkages, and bonding distances, they cannot be superimposed. Thus, in
the environment of living systems, where specific structure-activity
relationships may be required for effect (e.g., enzymes, receptors,
transporters, and DNA), the physiochemical and biochemical
properties of racemic mixtures and individual stereoisomers can
differ significantly. In drug development, enantiomeric selection to
maximize clinical effects or mitigate drug toxicity has yielded both
success and failure. Further complicating genetic polymorphisms
in drug disposition, stereoselective metabolism of chiral compounds can additionally influence pharmacokinetics, pharmacodynamics, and toxicity. Optically pure pharmaceuticals may
undergo racemization in vivo, negating single enantiomer benefits
or inducing unexpected effects. Appropriate chiral antidotes must
be selected for therapeutic benefit and to minimize adverse events.
Enantiomers may possess different carcinogenicity and teratogenicity. Environmental toxicology provides several examples in
which compound bioaccumulation, persistence, and toxicity show
chiral dependence. In forensic toxicology, chiral analysis has been
applied to illicit drug preparations and biological specimens, with
the potential to assist in determination of cause of death and aid in
the correct interpretation of substance abuse and ‘‘doping’’ screens.
Adrenergic agonists and antagonist, nonsteroidal anti-inflammatory
agents, SSRIs, opioids, warfarin, valproate, thalidomide, retinoic
acid, N-acetylcysteine, carnitine, penicillamine, leucovorin, glucarpidase, pesticides, polychlorinated biphenyls, phenylethylamines, and additional compounds will be discussed to illustrate
important concepts in ‘‘chiral toxicology.’’
Key Words: antidotes; chiral; ecotoxicology; forensic toxicology;
stereoisomer; teratology.
1
To whom correspondence should be addressed at Department of Emergency
Medicine, Bellevue Hospital Center, 462 First Avenue, Room A-345A, New
York, NY 10016. Fax: (212) 447-8223. E-mail: [email protected].
This manuscript was developed from a presentation at the American College
of Medical Toxicology Spring Conference, San Diego, CA, USA, March 2008.
The author has no financial interest in any commercial products mentioned
nor the companies that produce them. The use of trade names and/or
commercial products in this review is for identification purposes only and
constitutes neither a recommendation nor an endorsement for use by the author,
the New York University School of Medicine, or the New York City Poison
Control Center. No outside funding was received.
As mechanisms of toxicity are elucidated, precise structureactivity relationships have become more apparent. This review
introduces the concept of ‘‘chiral toxicology’’—the diverse
impact of chirality on multiple aspects of toxicology. An
historical overview and review of chemical principles guide an
exposition of chiral illustrations in drug development, stereoselective metabolism and toxicity, chiral antidotes, carcinogenicity, reproductive toxicology, environmental toxicology, and
forensic toxicology.
HISTORY
The study of chirality and symmetry has spanned the
disciplines of chemistry, biology, and physics. Early work by
Arago (1811) and Biot (1812a,b) demonstrated the effects of
cut crystals on the plane of polarized light—different crystals
rotated light left or right. Biot later showed that natural organic
products, such as oil of turpentine, sugar solutions, camphor,
and tartaric acid could produce similar rotation. In 1848,
Pasteur recrystallized the racemic sodium ammonium salt of
tartaric acid and noted two different crystal forms. Using
tweezers, he separated them, and after redissolved them, found
that they rotated polarized light differently (Pasteur, 1848).
Subsequently, in 1857 Pasteur made the first observation of
biological enantioselectivity, when he noted bacterial capacity
to ferment only dextro-tartaric acid (Gal, 2008; Pasteur, 1857).
In 1874, Van’t Hoff, recipient of the first Nobel Prize in
Chemistry, and Le Bel independently outlined the relationship
between three-dimensional molecular structure and optical
activity and the concept of the asymmetric carbon atom (Le
Bel, 1874; van’t Hoff, 1874). In 1891, Fisher performed the
unbelievable feat of identifying the 16 different spatial
configurations of aldohexose (C6H12O6), the most prominent
member being D-glucose (Fischer, 1891). He created eponymous Fisher projections to represent their threedimensional structure (and was awarded the second Nobel
Prize in Chemistry).
The physiological and toxicological significance of chiral
compounds was soon explored. Dextro-cocaine was found to
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CHIRAL TOXICOLOGY
have greater activity and more rapid onset, and shorter duration
than levo-cocaine (Ehrlich and Einhorn, 1894; Poulson, 1890).
Differences in atropine (racemic hyoscyamine) and levohyoscyamine on pupillary, cardiac, and salivary activity and
effects on frog spinal cord reflexes were described in 1903
(Cushny, 1903). Differences in toxic dose were reported for
nicotine isomers in 1904 (Pictet and Rotschy, 1904) and for
camphor isomers in 1910 (Grove, 1910). Exploring endogenous compounds, Abderhalden and Mu¨ller (1908) described
the significant differential vasopressor effects of levo-and
dextro-epinephrine. Therapeutically, Frey (1918) reported that
quinidine, the isomer of quinine, was more effective in treating
dysrhythmias.
CHEMICAL PRINCIPLES
Definitions and Terms
Isomers are compounds with the same molecular formula but
different structural formulas or different spatial arrangement
(Fig. 1A). Methoxybenzene (anisole), phenylmethanol (benzyl
alcohol), 2-methylphenol (ortho-cresol), 3-methylphenol
(meta-cresol), and 4-methylphenol (para-cresol) are examples
of constitutional or structural isomers. Although they share the
same molecular formula (C7H8O) and molar mass, their atoms
are linked differently (Fig. 1B), and they differ in physical
properties. A chiral object contains an asymmetric point, often
a carbon atom with different substituents, such that there can
be two nonsuperimposable forms in three-dimensional space
(Fig. 1C). Stereoisomers (spatial isomers) are compounds that
share identical molecular formulas, atom-to-atom linkages, and
bonding distances, but differ in their three-dimensional
arrangement. Diastereomers are stereoisomers which are
nonsuperimposable, non-mirror images. Enantiomers are
stereoisomers which are nonsuperimposable, mirror images.
They have identical physical and chemical properties except
when they interact with chiral systems. Enantiomers rotate the
plane of polarized light in opposite directions and by equal
amounts. For example, levo- and dextro-ephedrine are
enantiomers—they are mirror images, nonsuperimposable,
and rotate light in opposite directions by equal amounts.
Similarly, levo- and dextro-pseudoephedrine are enantiomers
of each other. Pseudoephedrine and ephedrine are diastereomers. All contain the same number and type of atoms and
bonding distances; all are ‘‘chiral’’ compounds. Cis-trans
isomers are stereoisomers arising from compounds with
restricted rotation (e.g., containing double bonds or some
alicyclic compounds). Cis-diastereomers have substituent
groups projecting in the same direction; trans-diastereomers
have substituents oriented in opposing directions (Fig. 2A).
Conformational isomers (conformers) are stereoisomers due
to bond rotation. Acetylcholine is an example of a rotamer
(conformer that differs by restricted rotation about only
a single bond): the gauche forms are conformers of each other
5
(Fig. 2B) (International Union of Pure and Applied Chemistry
[IUPAC], 1997). The 1,4-benzodiazepines typify ring inversion isomers. The seven-membered nonplanar ring can
take on two possible ‘‘boat’’ formations that are conformational isomers of each other (Fig. 2C) (Paizs and Simonyi,
1999). Rotational barriers induced by large substituent groups
may prevent rotation at low energy levels. Polychlorinated
biphenyls (PCBs) are a good example of atropisomers—
stereoisomers resulting from hindered rotation about single
bonds, where the steric strain barrier to rotation is high
enough to allow for the isolation of the separate conformers
(e.g., Fig. 8C) (IUPAC, 1997).
Several terms are commonly utilized to describe enantiomer
proportions within a given mixture (Fig. 3). The enantiomer
ratio (ER ¼ E1/E2) and enantiomer fraction [EF ¼ E1/(E1 þ
E2)] convey similar information, but must be interpreted
appropriately. The enantiomer excess [e.e. ¼ jE1 - E2j, where
E1 þ E2 ¼ 1 (or 100%)] is defined as the absolute difference
between the mole or weight fraction of each enantiomer, and
is commonly expressed as a percentage (IUPAC, 1997).
A racemate (racemic mixture) represents the unique case of
a perfect 1:1 (equimolar, e.e. ¼ 0) mixture of enantiomers.
Thus, it yields no optical rotation. Enantiomer proportions may
change over time under certain experimental, physiological, or
environmental conditions.
Nomenclature
Confusion arises from the multiple methods of naming
chiral entities. The oldest d- (dextro, symbolized as ‘‘þ’’), l(levo, symbolized as ‘‘’’) terminology arose to describe how
each specific enantiomer affected polarized light (Pasteur,
1848). When linearly polarized light passes through and
interacts with an enantiomer sample, it undergoes ‘‘optical
rotation.’’ If the enantiomer rotates the plane (of polarized
light) to the right, it is termed dextro-rotary (þ). If it rotates
the plane to the left, it is levo-rotary () (Fig. 4A).
Enantiomers’ dextro- or levo-rotation are equal in absolute
magnitude but opposite in direction. Importantly, the dextroor levo-rotation by each enantiomer has no correlation with
the actual assignment of its atoms in space, and thus no
relation to D/L or R/S naming conventions. For this reason,
a compound’s (±) optical activity may be provided alongside
its D/L or R/S name. Fisher developed the D/L system as
a means to describe carbohydrate stereoisomers (Fischer,
1891). It is also commonly applied to amino acids. ‘‘D’’ or
‘‘L’’ is assigned by relating a molecule to (chiral) glyceraldehyde. The molecule is written in a Fisher projection. One
aligns a given molecule with the carbon in the highest
oxidation state superiorly. At the chiral center closest to the
bottom, if the substituent (e.g., OH) projects to right, it is
classified as the D-isomer. If the substituent projects to left, it
is the L-isomer (Fig. 4B). The Cahn-Ingold-Prelog (CIP)
System (R- [rectus], S- [sinister] convention) or ‘‘absolute
configuration’’ is assigned by assigning ‘‘priority’’ to the
6
SMITH
FIG. 1. (A) Classification of isomers. (B) Constitutional (structural) isomers of C7H8O. (C) A chiral structure with two nonsuperimposable forms (W 6¼ X 6¼
Y¼
6 Z).
groups attached to the stereocenter (by highest atomic number
of the most proximate substituent and additional rules) (Cahn
et al., 1956, 1966; Prelog and Helmchen, 1982). One then
‘‘looks down’’ the substituent with the lowest priority to
determine if the decreasing order of the remaining groups
occurs in a clockwise (R) or counterclockwise (S) fashion
(Fig. 4C). R/S assignment does not always parallel D/L
assignment. The E- (entgegen), Z- (zusammen) system
describes more complex cis-trans configurations. CIP priorities are assigned to the substituents at each end of a rotational
barrier. The (Z)-isomer has higher priorities groups on the
same side; the (E)-isomer has two groups with the higher
priorities on opposite sides (Fig. 4D). Endo- and exodesignations are applied to substituents of molecules which
contain bridges. In endo-isomers, the group is towards (cisto) the longest bridge; exo-isomers are oriented away from the
longest bridge (e.g., Fig. 7A). M (minus) and P (plus)
designations for ring conformers such as diazepam are
assigned on the basis of the characteristic torsion angle of
C2-C3-N4-C5 of the diazepam ring (Fig. 2C) (Paizs and
Simonyi, 1999). Confusingly, P (plus, right-handed, clockwise, D)- and M (minus, left-handed, counterclockwise, K)
designations are also applied to supramolecular systems that
are helical, propeller, or screw-shaped (Fig. 4E) (IUPAC,
1997).
CHIRAL PHARMACOLOGY
Drug Development
FDA initial guidance on chiral drugs was set forth in 1992,
as the differential actions and toxicities of enantiomers became
more evident, and as the technology for chiral drug development and detection advanced (U.S. Food and Drug
Administration, 1992). Identified chiral-specific issues included
appropriate manufacturing controls (exclusion of diastereomeric impurities), product stability (racemization during
storage), pharmacokinetic evaluations and quantifications that
accounted for chiral differences (different dose-response
curves), and correct interpretation of data when the pharmacokinetic properties of isomers in animal models differed from
humans. According to the guidelines, composition of a chiral
drug had to be known when applied in pharmacological,
toxicological, and clinical studies.
In part because of the burdens associated with determining
the profiles and toxicities of mixed compounds, racemates have
CHIRAL TOXICOLOGY
7
FIG. 2. (A) Cis-trans isomerism arising from the different position of atoms (or groups) around a reference point (platinum atom), a carbon-carbon double
bond, and a cyclic structure (cycloalkane). (B) Acetylcholine conformers (rotamers) The gauche forms (seen in Newman projection) are conformers. (C) Two
conformations of diazepam which interconvert via ring inversion.
virtually disappeared from development as new molecular
entities. Single enantiomer or achiral drugs now dominate
newly approved drugs in the United States and abroad (Agranat
et al., 2002; Caner et al., 2004) Additionally, drugs previously
granted patent protection and marketed as racemates are
candidates for a ‘‘chiral switch’’ (i.e., development as single
or paired enantiomers (in the case of diasteromic mixtures),
which permits additional years of market exclusivity (Agranat
et al., 2002). Economic forces (e.g., market share) and
favorable clinical profiles have driven successful chiral
switches such as esomeprozole, levofloxacin, and escitalopram
(Fig. 6A), and racemic veterinarian compounds (medetomidine) have been adapted for human use ((S)-dexmedetomidine)
(Table 1). Antiviral analogues (abacavir, didanosine, lamivudine, stavudine, vidarabine, zidovudine, etc.) are produced as
single isomers such that their ring substitutions mimic the
2R,5R architecture of the ‘‘natural’’ nucleosides (adenosine,
cytidine, guanosine, thymidine, etc.). Compounds may contain
atypical amino acid isomers or their derivatives (e.g., D-serine
in goserelin). Other examples of current chiral pharmaceuticals
from a range of pharmaceutical classes are provided in Table 1.
These comprise drugs in which the enantiomer was developed
primarily, ‘‘chiral switches,’’ and drugs offered only as
enantiomers because the other isomer has no clinical effect
or adverse effects in vivo (e.g., Levodopa and levothyroxine).
Ideally, therapeutic activity would reside in one enantiomer
and adverse effects in the other. Unfortunately, there is a range
of possibilities, and the combined actions of the individual
enantiomers may actually make the racemate or enantiomer
combinations desirable. For example, when racemic dobutamine is administered, the nonselective b1 and b2 agonism by
the l-dobutamine enantiomer is moderated by the a1 agonism
of d-dobutamine to yield a clinical effect of apparent
b1-selectivity (Majerus et al., 1989; Ruffolo, 1987). Alternatively, an individual enantiomer may retain the racemate’s
undesirable activities, lose desired activity, or present new
8
SMITH
FIG. 3. Distinctions between the terms used to convey enantiomer
proportions. In a mixture composed of 75% of enantiomer 1 (E1) and 25%
of enantiomer 2 (E2), the enantiomer ratio (ER ¼ E1/E2) ¼ 75%/25% ¼ 3.0,
the enantiomer fraction [EF ¼ E1/(E1 þ E2)] ¼ 75%/(75% þ 25%) ¼ 0.75
(or 75%), and the enantiomer excess [e.e. ¼ jE1 E2j, where E1 þ E2 ¼ 1 (or
100%)] ¼ j75% 25%j ¼ 0.5 (or 50%).
toxicities. R()-salbutamol (albuterol) is responsible for
bronchodilator effects. S(þ)-salbutamol has little bronchodilating activity, actually causes hyperkalemia, and has been
implicated in eosinophil activation and pro-inflammatory
properties (Vakily et al., 2002). Unfortunately, R()-salbutamol
(introduced as levalbuterol) retains the undesirable side effects
of hypokalemia, hyperglycemia, tachycardia, and QT prolongation, and its clinical superiority is debated (Anonymous,
2006; Boulton and Fawcett, 1997; Vakily et al., 2002). Chiral
drug development has produced several disappointments.
Dexfenfluramine, an early chiral switch, retained the risk of
pulmonary hypertension and valvular heart disease in combination with phentermine and was withdrawn along with
racemic fenfluramine in 1997 (Anonymous, 1997). Dilevalol,
the (R,R) stereoisomer of labetalol (which has two stereocenters), avoided postural hypotension due to its lack of alphaadrenergic receptor antagonism, but was associated with an
increased risk of hepatotoxicity compared with labetalol and
was not approved by the FDA (Scott, 1993; Walgren et al.,
2005). Increased mortality in patients given d-sotalol—a class
III anti-dysrhythmic essentially devoid of the beta-antagonism
of the racemate—led to termination of the SWORD trial
(Waldo et al., 1996). Development of the active isomer (R)fluoxetine ceased after dose-dependent QTc prolongation
emerged in clinical trials, and its efficacy compared with
racemic fluoxetine was questioned (Dorey, 2000).
To complicate matters, chiral selection can be short-circuited
and efficacy and toxicity data misinterpreted if a drug undergoes chiral inversion—the conversion of one enantiomer into
its opposite (e.g., Fig. 7B) (Ali et al., 2007; Wsol et al., 2004).
In vivo, this normally occurs with the assistance of an enzyme
catalyst. Drugs from a variety of therapeutics classes that
undergo chiral inversion have been reviewed (Ali et al., 2007;
Wsol et al., 2004). Ibuprofen and other arylpropionic acid
derivatives are well-described molecules capable of chiral
inversion (Hao et al., 2005; Wsol et al., 2004). (S)-ibuprofen
inhibits COX1 and COX2 equally. The (R)-enantiomer weakly
inhibits COX1 and has no effects on COX2. However, an (R)metabolite, (R)-ibuprofenoyl-CoA, actually has greater COX2
inhibition. A majority of (R)-ibuprofenoyl-CoA undergoes
unidirectional conversion to active (S)-ibuprofen (Knihinicki
et al., 1991; Wsol et al., 2004). (R)-ibuprofen thus functions as
a pro-drug and contributes to therapeutic effects (Neupert et al.,
1997). In contrast, ketorolac (acetic acid derivative) displays
species-specific interconversion—71% in mice and 12% in
rats. Human inter-conversion is minimal—0% R(þ)-ketorolac
to S()-ketorolac and 6% S()-ketorolac to R(þ)-ketorolac
(Mroszczak et al., 1996). Thus, animal models might overestimate or underestimate efficacy if significant interconversion
occurs. Age-dependent and enantiomer-specific elimination
occurs with ketorolac—clearance in children is twice that of
adults and clearance of active (S)-enantiomer is four times that
of inactive (R)-isomer (Kauffman et al., 1999). This would
suggest that higher weight-adjusted doses would be required to
achieve comparable plasma concentrations of the active isomer
in children. Nonstereospecific assays would also tend to
misconstrue the duration of effect.
Biological Implications: Metabolism and Clinical Effects
Biological systems are chiral entities. Humans are primarily
composed of L-amino acids and D-carbohydrates. Protein
secondary structure includes right-handed (P-) coiled alpha
helices, and most DNA is similarly in a right-handed spiral
configuration (termed ‘‘B-DNA,’’ as opposed to left-handed
‘‘Z-DNA’’) (Fig. 4E) (Dickerson et al., 1982). Tertiary
structures create unique three-dimensional binding, catalytic,
and stabilization domains (Fig. 5). On the macroscopic scale,
during normal growth and development both the human
cardiac and gastrointestinal systems have specific rotational
patterns, and additionally, left-right ‘‘mirror’’ symmetry
evolves. Unique structural-activity relationships thus proceed
from specific architecture constraints at multiple systemic
levels. Therefore, in a chiral environment, stereoisomers might
experience selective absorption, protein binding, transport,
enzyme interactions and metabolism, receptor interactions, and
DNA binding. Thus, each stereoisomer or isomeric mixture can
have different pharmacokinetic, pharmacodynamic, therapeutic, and adverse effect profiles. A given structure’s capacity to
accommodate chiral disparities will influence the magnitude
and type of difference in effects (if any) observed between
enantiomers. For example, one enantiomer might be completely unable to complex with a particular receptor or enzyme
or lose precise alignment at a catalytic site, whereas at
a different molecule, no impairment might occur (Fig. 5).
These consequences of stereospecificity have been reported for
multiple pharmaceutical classes including antibiotic, cardiovascular, chemotherapeutic, psychotropic, pulmonary, and
rheumatic drugs (Baker and Prior, 2002; Hutt and O’Grady,
1996; Kean et al., 1991; Mehvar et al., 2002; Ranade and
CHIRAL TOXICOLOGY
9
FIG. 4. Stereoisomer naming conventions. (A) According to optical activity: incoherent light is passed through a polarizer lens and then through a tube
(polarimeter tube) containing a sample of the enantiomer. The degree of rotation of polarized light by an enantiomer is determined by an analyzer—a rotatable
polarizer lens—in conjunction with a detector. Dextro-rotary (þ) compounds rotate the polarized light plane to the right (clockwise), levo-rotary (–) compounds to
the left (anti-clockwise). (B) The d/l (Fischer) naming convention for glyceraldehydes—the asterix denotes the substituent determining D- or L-assignment. (C and D)
The CIP R/S- and E/Z-naming conventions according to priority of substituents. (E) The IUPAC P,M-naming conventions of helical, propeller, or screw-shaped
structures.
Somberg, 2005; Vakily et al., 2002; Wainer and Granvil, 1993;
Williams, 1990).
Absorption/carriers. The drug efflux transporter Pglycoprotein, which participates in drug absorption, distribution, and excretion, is regulated stereospecifically. For
example, R-cetirizine upregulates P-glycoprotein expression,
while S-cetirizine down-regulates it (Shen et al., 2007).
P-glycoprotein is enantioselectively inhibited by the levo-isomer
of mefloquine, which can affect the transport of P-glycoprotein
substrates such as cyclosporine and vinblastine (Lu et al.,
2001; Pham et al., 2000). The human reduced folate carrier is
stereospecific for the natural (6S) stereoisomer of 5-formyl
tetrahydrofolate (leucovorin) and the antifolate methotrexate
(Matherly and Hou, 2008; Narawa et al., 2007). Stereospecific
transport contributes to methyl mercury central nervous system
(CNS) toxicity. Methyl mercury binds cysteine to generate
methyl mercury-cysteine [CH3-Hg-S-CH2-CH(NH2)COOH].
The structure’s mimicry of methionine [CH3-S-CH2-CH2CH(NH2)COOH] permits L-type large neutral amino acid
10
SMITH
TABLE 1
Chiral Pharmaceuticals and Parent Racemates
Isomer
Armodafinil (Nuvigil)
Betamethasone (many)
Cisatracurium (Nimbex)
Desloratadine (Clarinex)
Dexamethasone (many)
Dexchlorpheniramine
(Polaramine, non-US)
ˆ
Dexmedetomidine (PrecedexO)
Dexmethylphenidate (Focalin)
Dextroamphetamine (Dexedrine)
Dextromethorphan (many)
Escitalopram (Lexapro)
Esomeprazole (Nexium)
Eszopiclone (Lunesta)
Levalbuterol (Xopenex)
Levobetaxolol (Betaxon)
Levobunolol (Betagen)
Levocabastine (Livostin)
Levocetirizine (Xyzal)
Levodopa (with carbidopa
as Atamet, Sinemet)
Levofloxacin (Levaquin)
Levonorgestrel (Alesse,
Seasonale, Plan B, etc.)
Levorphanol (Levo-Dromoran)
Levothyroxine (Synthroid,
Levoxyl, etc.)
Technetium Tc99m Bicisate
(Neurolite)
Racemate
Modafinil (Provigil)
N.A. (16S isomer of dexamethasone)
Atracurium (Tracrium)
Loratadine (Claritin)
N.A. (16R isomer of Betamethasone)
Chlorpheniramine (Chlor-Trimeton, etc.)
Medetomidine (Dormitor, veterinary)
Methylphenidate (Ritalin, etc.)
Amphetamine (Adderall)
N.A.
Citalopram (Celexa)
Omeprazole (Prilosec)
Zopiclone (sold outside United States)
Albuterol (Proventil, Ventolin, etc.)
Betaxolol (Betopic)
N.A.
N.A
Certirazine (Zyrtec)
N.A.
Ofloxacin (Floxin)
Norgestrel (Lo/Ovral, Cryselle, etc.)
N.A.
N.A.
N.A.
carrier-mediated transport across the blood brain barrier
(Clarkson et al., 2007). Methyl mercury-L-cysteine uptake
significantly exceeds that of methyl mercury-D-cysteine
(Kerper et al., 1992; Mokrzan et al., 1995). At certain
concentrations, S()-bupivacaine has a vasoconstrictor effect
absent in the R(þ)-isomer, which results in drug remaining at
the injection site and a longer duration of analgesia (Aps and
Reynolds, 1978). Levobupivicaine (Chirocaine), which did not
carry the ‘‘black box’’ warning for cardiotoxicity required of
racemic bupivacaine, has been discontinued in the United
States (U.S. Food and Drug Administration, 2008).
Protein binding. Chirality may influence the basic pharmacological property of protein binding. Albumin has speciesspecific, stereo-specific binding preferences (Pistolozzi and
Bertucci, 2008). Despite diazepam’s rapid interconversion
(Fig. 2C), its M-form prevails when bound to albumin.
Bilirubin, which is achiral in solution due to rapid interconversion of its M- and P-forms, binds albumin in the
P-form (Pistolozzi and Bertucci, 2008). Human albumin prefers
the active S-enantiomer of ketoprofen and has stereoselectivity
to other non-steroidal anti-inflammatory drugs (NSAIDs).
Human albumin also displays stereoselective binding to
FIG. 5. (A) An hypothetical enantiomer (Enantiomer1) interacting with
a hypothetical enzyme structure (Target1), where domain A# is a catalytic site,
B# is a hydrophobic pocket, and C# and D# are areas of steric hindrance.
Enantiomer1 can effectively bind within the structure’s architecture and achieve
appropriate orientation at the catalytic site. (B) Regardless of what rotational
position Enantiomer2 assumes, it is incapable of appropriately aligning with
either the active or stabilization domains (i.e., to avoid the steric hindrance
imposed by D# on C, A is displaced away from the catalytic site A#, and B–B#
interactions are not as efficient). (C) If a structure’s architecture is less
constrained (e.g., Target2), then effective interactions may occur.
warfarin (Fitos et al., 2002; Tatsumi et al., 2007). Albumin
binds S(þ)-chloroquine more avidly than R()-chloroquine,
whereas alpha-1-acid glycoprotein binds the R-enantiomer
more tightly (Augustijns and Verbeke, 1993; Ofori-Adjei et al.,
1986). Alpha-1-acid glycoprotein has stereospecific affinity for
R()-disopyramide, S()-verapamil, and R(þ)-propranolol
CHIRAL TOXICOLOGY
(Hanada et al., 2000), and preferably binds the P-conformer of
diazepam (Fitos et al., 2007). Correct interpretation of
pharmacokinetic data and pharmacokinetic model constructs
may be compromised if species-specific and enantiomerspecific differences in protein binding are not accounted for.
The implications of stereoselective protein binding, bioequivalence, and the employment of stereospecific assay techniques
are reviewed by Brocks (2006), Srinivas (2004), and others. In
an organism provided a racemic ‘‘drug,’’ nonstereospecific
assays would attribute an observed effect to the total free
‘‘drug’’ even if isomers had markedly dissimilar binding
properties (e.g., protein binding of 65% in isomer R and 35% in
isomer S would yield apparent ‘‘drug’’ binding of 50%). The
correct clinical or adverse effect dose-response relationship
would be misinterpreted if R/S isomer activity differed. As only
free or unbound drug participates in elimination or receptor
interaction, observed clearance, apparent volume of distribution, tissue distribution, and duration of effect might be further
misconstrued, particularly as isomer ratios changed over time.
Dose calculations and dosing intervals derived from a test
species could be incorrect if humans or other species displayed
alternative stereo-specific binding preferences (particularly of
an active isomer) (Tocco et al., 1990). Thus, considering each
stereoisomer as a distinct chemical entity refines pharmacokinetic models of racemates and mixtures.
Metabolism and elimination. As might be expected for
enzymatic processes, the biotransformation reactions (e.g.,
hydrolysis, reduction, oxidation, and conjugation) may demonstrate isomeric preference. (S,S)-hydroxybupropion is stereoselectively active at dopamine transporters, norepinephrine
transporters, and nicotinic acetylcholine receptors (Damaj
et al., 2004). At therapeutic concentrations, CYP2B6-mediated
hydroxylation of (S)-bupropion to metabolically active (S,S)hydroxybupropion is significantly greater than (R)-bupropion,
leading to greater apparent oral clearance and lower plasma
concentrations (Kharasch et al., 2008). (S,S)-hydroxybupropion
is formation-rate-limited, whereas (R,R)-hydroxybupropion
and racemic hydroxybupropion are elimination-rate-limited;
thus, CYP2B6 phenotypic variability, inhibition or induction,
or overdose might alter the clinical consequences of bupropion
ingestion (Kharasch et al., 2008). Hepatic, jejunal mucosa, and
platelet sulfation of R()-salbutamol (albuterol) is approximately ten times greater than the S(þ)-isomer (Walle et al.,
1993). The (S)-enantiomer of carvedilol undergoes stereoselective oxidation by cytochrome P450 (CYP) 2D6 and
CYP1A2 in liver and stereoselective glucuronidation in liver
and intestine, which is at least partly responsible for stereoselective presystemic clearance (Ishida et al., 2008). CYP2C19
preferential metabolism of S()-lansoprazole is further influenced by polymorphism status (homozygous and heterozygous
extensive metabolizers, and poor metabolizers), such that the
R/S ratios for the lansoprazole AUC in these polymorphisms is
12.7, 8.5, and 5.8, respectively, after oral dosing (Miura, 2006).
11
Similarly, systemic R/S enantiomer exposures to fluoxetine,
metoprolol, pantoprozole, and trimipramine are altered according to CYP2D6 or CYP2C19 status (Brocks, 2006). CYP2D6
stereoselectively catalyses the O-demethylation of (R)venlafaxine (Eap et al., 2003). Stereoselective drug metabolism
and elimination has been reported for a numerous other
compounds: ketamine, whose R()-ketamine inhibits the more
rapidly clearing S(þ)-ketamine; (S)-pentoxifylline conversion
to its M1 metabolite; tramadol N-demethylation to S(–)-Odemethyltramadol; renal tubular secretion of dextro-cetirizine;
and clearance of verapamil isomers (Garcia Quetglas et al.,
2007; Ihmsen et al., 2001; Nicklasson et al., 2002; Schwartz
et al., 1994; Strolin Benedetti et al., 2008; Williams and
Wainer, 2002). From a therapeutic standpoint, proteaseresistant, cell-penetrating peptides are being developed for
drug delivery through incorporation of D-amino acids (Pujals
et al., 2008).
Receptor (target) interactions. There are multiple examples of varied receptor types with chiral dependence. Vision
itself requires cis-trans isomerism (Fig. 2A). 11-cis-retinal
isomerizes to all-trans-retinal upon light absorption (Fig. 7C
depicts analogous cis-trans isomers of retinoic acid in clinical
use). This produces a conformational change within rhodopsin
to yield activated metarhodopsin II, with subsequent triggering
of the G-protein second messenger cascade and transmission of
the photoactivation signal (Ahuja et al., 2009). Levo-carvone is
perceived as spearmint, whereas dextro-carvone provides
a caraway aroma (Williams and Wainer, 2002). R(þ)limonene, an essential oil employed as a food and cosmetic
additive, solvent, and cleaning product generates a pleasant
lemon-orange scent; S()-limonene smells like turpentine
(IARC Working Group on the Evaluation of Carcinogenic
Risks to Humans, 1999). Both may produce allergic reactions
(Heydorn et al., 2003). Dextromethorphan primarily provides
an anti-tussive effect, although levomethorphan, a noncommercially available DEA schedule 2 compound, has classic, potent
systemic opioid effects. The conformers of acetylcholine (Fig.
2B) are physiologically relevant. It appears that the anti and
gauche forms demonstrate variable affinity to nicotinic and
muscarinic receptor subtypes, and the anti form is the
preferential conformation for acetylcholinesterase catalysis
(Edvardsen and Dahl, 1991; Lin et al., 2007; Vistoli et al.,
2007). D-Serine coagonizes the N-methyl D-aspartate receptor
(Wolosker et al., 2008). The antiepileptic S(þ)-vigabatrine
irreversibly inhibits gamma- aminobutyric acid (GABA) transaminase, whereas the R-enantiomer is without activity (Gidal
et al., 1999). Complicating matters, a xenobiotic may have
stereospecificity at certain receptors, but not others (Fig. 5). S(
)-propranolol exhibits approximately 100 times greater antagonism than R(þ)-propranolol at b1, b2, and b3 receptors (Popp
et al., 2004; Ranade and Somberg, 2005). S()-propranolol is
also up to four times more bioavailable and has a longer half-life,
with stereoselective binding to human alpha 1-acid glycoprotein
12
SMITH
(Walle et al., 1983). However, the ‘‘membrane stabilizing
effect’’ and inhibition of thyroid hormone conversion are equal
between the two enantiomers (Scott, 1993). Target selectivity
also includes DNA. Transplatin (Fig. 2A), the isomer of the
chemotherapeutic cisplatin, is without significant chemotherapeutic effect. This may be due to variable efficiency in forming
DNA-protein cross-links, the different structure and stability of
the DNA-protein adducts once formed, and solubility differences in aqueous media (Boudvillain et al., 1995; Kasparkova
et al., 2008; Marchan et al., 2004)
Chiral Pharmaceuticals: Clinical Toxicological Correlations
Citalopram. Escitalopram, the active enantiomer, is a commercially successful chiral derivation from racemic citalopram
(Fig. 6A). CYP 3A4 and CYP 2C19, and CYP 2D6 demethylate
of escitalopram to (S)-desmethylcitalopram and (S)-didemethylcitalopram. There is wide inter- and intrapatient variability in
escitalopram serum concentrations (Reis et al., 2007). Because
of its serotonergic activity, escitalopram retains the ability to
cause hyponatremia, serotonin syndrome, and restless leg
syndrome (Covyeou and Jackson, 2007; Forest Pharmaceuticals,
Inc. 2009; Grover et al., 2007; Huska et al., 2007; Nahshoni
et al., 2004; Olsen et al., 2004; Page et al., 2008; Vari and
Beckson, 2007) Both the S- and racemic citalopram prolong
the QT equally and slightly more than placebo, and the
manufacturer reports both QT prolongation and rare cases of
torsade de pointes (Forest Pharmaceuticals, Inc. 2009). QT
prolongation may be delayed for up to 10-h postingestion in
escitalopram overdose, mandating prolonged cardiovascular
monitoring (Yuksel et al., 2005). Thus, clinical superiority of
escitalopram appeared undemonstrated in a review: despite the
ability to take a lower absolute daily dose, the adverse effect
profiles and cost are effectively similar (Anonymous, 2002).
Methadone. Methadone use has been associated with
prolonged QT interval and torsades de pointes (Ehret et al.,
2006; Pearson and Woosley, 2005). Clinician unawareness of
this risk led to pretreatment and ongoing electrocardiogram
screening guidelines for patients prescribed methadone (Krantz
et al., 2009). Opioid activity resides in the methadone R()enantiomer; temperature-dependent hERG potassium channel
inhibition resides primarily with the S(þ)-enantiomer (IC50 of
2lM) (Fig. 6B) (Eap et al., 2007). Methadone is primarily
metabolized by N-demethylation to an inactive metabolite
EDDP
(2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene)
(Gerber et al., 2004). In a complex fashion, stereoselective
cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and
CYP2C19, and to a lesser extent CYP2C9 and CYP2D6,
convert methadone to EDDP and other inactive metabolites
(Gerber et al., 2004; Totah et al., 2007). At CYP3A4, both
R()- and S(þ)-enantiomers are metabolized equally, but when
given as a racemate, there is mutual competitive inhibition,
which results in equal decreased clearance. At therapeutic
concentrations of each individual enantiomer, CYP2B6
FIG. 6. Examples of chiral pharmaceuticals—the asterix (*) denotes the
chiral atom. (A) Racemic citalopram and escitalopram. (B) R- and Smethadone. (C) R- and S-warfarin. Upon ketoreductase reduction of the ketone
(#) to warfarin alcohol, an additional chiral carbon is generated.
metabolizes (S)-methadone faster; at higher concentrations,
the (R)-enantiomer reaction proceeds faster. However, with the
racemate, the (R)-enantiomer has virtually no effect on (S)methadone metabolism, where as (R)-metabolism is significantly retarded by (S)-, indicating stereo-preference for
(S)-methadone. At CYP2C19, with less overall metabolism,
just the opposite occurs, (R)- is more preferentially metabolized; again (S)- and (R)-inhibit each other’s metabolism. 2B6
genotype status—specifically the *6/*6 slow metabolizer—has
been associated with a reduced ability to metabolize (S)methadone, a higher mean heart-rate–corrected QT, and an
increased risk of prolonged QTc (Eap et al., 2007). A separate
pharmacokinetic study evaluating peak and trough methadone
levels in patients with various 2B6 genotypes also found (S)enantiomer concentrations could be achieved which could
significantly impair repolarization (Crettol et al., 2005). Thus,
genetic polymorphisms, coupled with dose-dependent stereochemistry might underlie the clinical toxicity seen with
methadone administration.
Warfarin. Warfarin has significant, divergent interpatient
metabolism and dosing requirements. Patients display a wide
dosing range to achieve the narrow therapeutic window
CHIRAL TOXICOLOGY
between overcoagulation (risking hemorrhagic complications)
and undercoagulation (risking thrombotic complications).
Warfarin is available only as a racemic mixture, although the
S()-isoform is significantly more potent (Fig. 6C) (Scott,
1993). Metabolic hydroxylation occurs at various locations
depending on the enantiomer (Au and Rettie, 2008; Kaminsky
and Zhang, 1997; Park, 1988). S()-warfarin metabolism
occurs via CYP2C9 (to 7-hydroxywarfarin, major contribution), CYP2C9 (to 6-hydroxywarfarin, moderate contribution);
CYP3A4 (to dehydrowarfarin, minor contribution); and
ketoreductase [to (S,S)-warfarin alcohol 2 minor contribution].
In comparison, R(þ)-warfarin metabolism proceeds by
CYP1A2 (to 6- and 8-hydroxywarfarin, moderate contribution); CYP2C19 (to 8-hydroxywarfarin, moderate contribution);
CYP3A4
(to
10-hydroxywarfarin,
moderate
contribution); CYP3A4 (to dehydrowarfarin, minor contribution); and ketoreductase [to (R,S)-warfarin alcohol 1, moderate
contribution]. Suppression or acceleration of the various CYP
enzymes involved by exogenous drugs can thus affect the
clearance of both (R)- and (S)-isoforms. Moreover, because the
(R)-enantiomer inhibits the metabolism of (S)-warfarin at
CYP2C9, impaired metabolism of (R)-warfarin may cause
increased levels of the active (S)-isoform. Complexity further
increases when known genetic heterogeneity is superimposed
upon interacting isomer and xenobiotic effects. CYP2C9 *2 and
*3 variants cause 30% and 80% reduced activity and require
lower warfarin doses. Additionally, a variable polymorphic
pharmacodynamic contribution from the vitamin K epoxide
reductase complex subunit (VKORC1) may also alter the R/S
ratio and contribute to warfarin resistance (Au and Rettie, 2008;
Osman et al., 2007; Rettie and Tai, 2006). The failure of
a CYP2C9 and VKORC1-only genotype-guided warfarin
dosing strategy to show benefit might in part be due to
inattention to these additional stereospecific interactions
(Anderson et al., 2007).
CHIRAL ANTIDOTES
Dextrose (D-glucose)
Dextrose is a common antidote routinely administered to
reverse hypoglycemia induced by organic or toxicological
cause (anti-diabetics, ethanol, quinine, salicylates, etc.). Most
glucose transporters, which are critical to growth, development,
and health, have a high affinity for D-glucose, and generally
negligible affinity for L-glucose (Fig. 4B, D/L conventions)
(Cunningham et al., 2006). L-Glucose cannot be metabolized
and does not show increased uptake in response to insulin in
human volunteers. Other diverse downstream effects of
D-glucose, such as upregulation of adenosine transport in
aortic smooth muscle cells, decrease in lymphocyte intracellular ionized magnesium, and fibroblast premature replicative
senescence do not occur if L-glucose is substituted (Blazer
et al., 2002; Delva et al., 2002; Leung et al., 2005; MacLean
13
et al., 2001). In vitro, glucose isomers alter hematocrit and
blood viscosity differently, due to erythrocyte uptake specificity for D-glucose (Buhler et al., 2001). Under conditions of
excess solute-free water, D-glucose causes erythrocyte swelling, as water follows D-glucose intracellularly; under initial
isotonic conditions, excluded L-glucose results in erythrocyte
shrinkage. L-Glucose does taste as sweet as D-glucose, presumably by presenting the same glycophore (two-dimensional
surface part) to the taste receptor (Shallenberger, 1997).
However, L-glucose is a significant laxative, which is likely
secondary to its limited oral and intestinal absorption (the
three-dimensional structure conferring transporter specificity),
with consequential induction of osmotic diarrhea (Fine et al.,
1993; Kimura et al., 2002; Raymer et al., 2003). D-Glucose is
also generally favored over other D-glucose epimers such as
D-mannose or D-galactose. Similarly sodium-coupled glucose
transporters show a much lower affinity for D-galactose than
D-glucose (Scheepers et al., 2004).
N-acetyl-L-cysteine (L-NAC)
N-acetylcysteine provides an effective means of prevention
and treatment of acetaminophen-induced hepatotoxicity, even in
cases of delayed presentation following overdose (Keays et al.,
1991; Smilkstein et al., 1988). L-NAC is also utilized to prevent
contrast induced nephropathy (Massicotte, 2008). Only the Lform is antidotally useful. In animal experiments, the L-isomer,
which is derived from physiologic L-cysteine, prevents
hepatotoxicity and provides prolonged elevations of hepatic
glutathione (Wong et al., 1986a). The nonphysiologic D-isomer
cannot increase glutathione stores or prevent hepatotoxicity,
despite increasing acetaminophen sulfation (Corcoran and
Wong, 1986; Wong et al., 1986b), L-NAC also has demonstrable extra-hepatic benefits—improving cardiac index
and systemic mean oxygen delivery despite decreasing
systemic vascular resistance (Harrison et al., 1991). Interestingly, only the L-isomer was capable of mediating vascular
tone—blunting tolerance to the hypotensive effect of glyceryl
trinitrate in rats (Newman et al., 1990). L-NAC was twice as
effective at inhibiting cell cycle progression and topoisomerase-IIa activity (Grdina et al., 1998). This would be protective
by interrupting cell division in the setting of inadequate
substrates or growth factors. L-NAC, but not D-NAC, provides
protection against ultraviolet light induced DNA damage in
cultured fibroblasts and retinal damage in vivo (Busch et al.,
1999; Morley et al., 2003). The unnatural D-NAC also resists
enzymatic degradation, limiting the useful liberation of
cysteine (De Flora et al., 1995; Sarnstrand et al., 1995).
L-Carnitine
L-(R)-carnitine is primarily used in the treatment of valproate
(VPA) toxicity (Lheureux et al., 2005; Russell, 2007). It is also
suggested for treatment of drug-associated mitochondrial
toxicity (e.g., from nucleoside analogs) and anthracycline
14
SMITH
cardiotoxicity (Claessens et al., 2003; Delaney et al., 2007;
Zeidan et al., 2002). Brain carnitine uptake is stereospecific for
L-carnitine (Huth et al., 1981), and the acetylated L-form can
serve as a precursor for releasable glutamate (Tanaka et al.,
2003). Although both D- and L-carnitine reduce the incidence
of murine ammonia-induced seizures, only L-carnitine lowered
ADP and AMP levels (Matsuoka and Igisu, 1993). Compared
with D-carnitine, L-carnitine also improved cardiac metabolic
function, oxygen consumption, and mechanical efficiency by
moderating free fatty acid metabolism (Liedtke et al., 1981,
1982). The D-isomer is considered biologically inactive and
harmful (Hathcock and Shao, 2006). It competitively depletes
serum and cardiac and skeletal muscles of L-carnitine
(Arancio et al., 1989; Ayala, 1995; Rebouche, 1983; Tsoko
et al., 1995), and competitively inhibits L-carnitine intestinal
uptake and renal reabsorption (Gross and Henderson, 1984).
Use of racemic D,L-carnitine was associated with myasthenialike syndromes (Bazzato et al., 1981; Clair et al., 1984;
Rossini et al., 1981) and cardiac arrhythmias, which
disappeared after L-carnitine administration. Toxic cardiac
effects of D-carnitine have been described in patients with
renal failure on long-term hemodialysis and in doxorubicin
cardiotoxicity. Neither the D-isomer nor the racemate should
be antidotally administered.
Physostigmine
Antidotal use of physostigmine (eserine) dates from 1864,
when it was reported to reverse severe poisoning secondary to
atropine ingestion (Nickalls and Nickalls, 1988). Physostigmine, a carbamate inhibitor, is derived from the seed (Calabar
bean) of the vine Physostigma venenosum Balfour, and was
used in the ancient trial by ordeal (Fraser, 1863). Although its
nonspecific analeptic properties are no longer considered useful
in sedative-hypnotic or tricyclic overdose, physostigmine is
currently recommended as a diagnostic and therapeutic agent
for antimuscarinic poisoning (Burns et al., 2000). Naturally
available 3aS()-physostigmine is over 100 times more
effective in inhibiting acetylcholinesterase and butylcholinesterase in tissue, erythrocytes, and serum in humans and animal
models (Atack et al., 1989; Barak et al., 2009; Brossi, 1985,
Brossi et al., 1986; Chen et al., 1992; Hill and Newkome,
1969; Petcher and Pauling, 1973; Yu et al., 1997). This
stereoselectivity was recently demonstrated to depend upon
asymmetric interactions within the acetylcholinesterase active
center hydrophobic pocket, which is distinct from the catalytic
site (Barak et al., 2009). Unexpectedly, at dosages which
insignificantly inhibited acetylcholinesterase, (þ)-physostigmine protects against lethal sarin exposures and inhibits sarininduced motor endplate postjunctional damage and myopathy
(Harris et al., 1990; Kawabuchi et al., 1988). This sarinprotective mechanism is apparently due to independent (þ)physostigmine antagonism at the nicotinic receptor. Physostigmine binding at nicotinic receptors is close to, but distinct from
the acetylcholine binding site on the a-subunit (Pereira et al.,
2002). At low doses, ()-physostigmine functions as an
ineffective receptor agonist, whereas at higher doses it
produces marked channel blockade (Militante et al., 2008).
In addition to antidotal considerations, a more complete
understanding the site-specific properties of stereoisomers of
physostigmine and its carbamate analogues (e.g., at acetylcholinesterase vs. the acetylcholine receptor) aims to further drug
development efforts to treat Alzheimer’s disease and myasthenia gravis.
Leucovorin
Leucovorin (folinic acid, 5-formyltetrahydrofolic acid) is
provided as rescue therapy to patients receiving high doses of
the antimetabolite antifolate methotrexate (MTX) and is used to
counteract MTX toxicity (Bleyer, 1977; Flombaum and
Meyers, 1999; Smith and Nelson, 2008). Endogenously
produced as l-leucovorin, it had been commercially available
only as the racemate until 2008, when levoleucovorin [(6S)leucovorin] received FDA approval (Spectrum Pharmaceuticals, 2008). Only the active S-form in racemic leucovorin is
metabolized to reduced folates (tetrahydrofolate, 5-CH3tetrahydrofolate, 10-CHO-tetrahydrofolate, and 5,10-CH2tetrahydrofolate) (Bunni and Priest, 1991). During intravenous
administration of the racemate, the active l-form (6S)
conversion into 5-methyl-tetrahdrofolate is rapid, whereas the
inactive isomer is slowly eliminated by renal excretion
(Schilsky and Ratain, 1990). Oral bioavailability of leucovorin
is poor above 40 mg and is negligible for the d-(6R)-form
(Bleyer, 1989; Schilsky and Ratain, 1990). The renal tubular
cell is the only cell where the inactive form is transported
actively; however, under circumstances of high or frequent
intravenous racemic leucovorin doses, d-leucovorin can
compete with and inhibit levoleucovorin passive transmembrane transport (Bleyer, 1989). Compared with the d-isomer,
levoleucovorin is 20 times more effective in inhibiting carriermediated membrane transport of methotrexate and 100-times
more effective in preventing MTX growth inhibition in murine
tumor cells (Sirotnak et al., 1979). As it is entirely active,
levoleucovorin is prescribed at one-half of the usual racemic
dose (Spectrum Pharmaceuticals, 2008). Levoleucovorin at this
dose appears to provide as efficacious rescue treatment as the
racemate in high dose MTX chemotherapy (Goorin et al.,
1995; Jaffe et al., 1993).
Glucarpidase
Glucarpidase (carboxypeptidase G2, CPDG2) is undergoing
evaluation as an antidote for methotrexate toxicity. This
bacterially derived enzyme cleaves glutamate residues from
methotrexate to render it inactive. Carboxypeptidase’s affinity
for methotrexate is 10- to 15-fold higher than for leucovorin; its
affinity for folate and 5-methyltetrahydrofolate (leucovorin’s
active metabolite) are similar (Albrecht et al., 1978; European
Medicines Agency [EMEA], 2008; Sherwood et al., 1985).
CHIRAL TOXICOLOGY
Active levo-(6S)-leucovorin is inactivated about 50% faster
than nonphysiologic dextro-(6R)-leucovorin by glucarpidase
(Hempel et al., 2005). The cleavage site is distinct from the
chiral carbon. Fifteen minutes after CPDG2 administration,
median leucovorin and active 5-methyltetrahydrofolate concentrations dropped by 8% and >97% (Widemann et al.,
1998). Remaining leucovorin was likely in the inactive d-form
(Widemann and Adamson, 2006). In healthy volunteers,
glucarpidase reduced active leucovorin and activated levo-5methyltetrahydrofolate exposures by 50 and 100% despite a
2-h window between drug administration (European Medicines
Agency [EMEA], 2008). Human in vivo glucarpidase activity
against active leucovorin and activated levo-5-methyltetrahydrofolate has been shown to persist for at least 26 h (European
Medicines Agency [EMEA], 2008). Because of this stereoselective destruction of active leucovorin and its metabolite,
many protocols separate leucovorin administration from
glucarpidase administration by 2–4 h.
Dexrazoxane
Following extravasation of anthracycline drugs, dexrazoxane
[S(þ)-1,2-bis(3,5-dioxopiperazin-1-yl)propane, ICRF-187] is
used to diminish tissue damage and need for surgical excision
of necrosis (Mouridsen et al., 2007). Its mechanism of action
appears to involve reversible inhibition of topoisomerase II and
inhibition by its metabolite, an ethylenediaminetetraacetic acid
analog, of free radical formation via iron removal from the
iron-doxorubicin complex (Hasinoff and Aoyama, 1999;
Reeves, 2007). For this reason, dexrazoxane is also used to
limit anthracycline-associated cardiomyopathy (van Dalen
et al., 2008). Dexrazoxane was developed due to the limited
solubility of racemic razoxane (ICRF-159) (Zhang et al.,
1994). In vitro, both dexrazoxane and its stereoisomer
levrazoxane (ICRF-186) are equally cytotoxic and inhibitory
toward DNA topoisomerase II (Hasinoff et al., 1995).
However, the enzyme dihydropyrimidine amidohydrolase in
liver and kidney stereoselectively catalyzes the first ringopening step in dexrazoxane versus levrazoxane, and can
subsequently open the second ring only in dexrazoxane, which
is required for activity (Hasinoff, 1994; Hasinoff and Aoyama,
1999) At lower doses, corresponding to those used clinically,
dexrazoxane improved survival in anthracycline treated
animals, and at some doses additionally demonstrated increased cardioprotection and a decrease in immune effector
cells (Hasinoff and Aoyama, 1999; Zhang et al., 1994). These
differences disappeared at higher doses.
D-Penicillamine
Penicillamine is used in the treatment of copper poisoning
and Wilson’s disease and has the advantage of oral availability.
D-(S)- and L-(R)-penicillamine chelate copper equally. Penicillamine is second- or third-line therapy for lead and mercury
poisoning. Differential toxicity of the L- and D-forms was
15
reported as early as 1948—L-penicillamine inhibited growth
and produced generalized seizures in rats (Wilson and Du
Vigneaud, 1948). The L-enantiomer was also associated with
impaired L-amino acid intestinal absorption (Wass and Evered,
1970), optic neuritis (Kean et al., 1991; Tu et al., 1963),
nephrotic syndrome (Sternlieb, 1966) and pyridoxine antagonism (Williams, 1990). Historically, in the United Kingdom,
only the D-form obtained from hydrolysis of penicillin was
used, whereas U.S. manufacturers originally synthesized
penicillamine from racemic valine (Walshe, 1992). Cases of
thrombocytopenia and leukopenia became less prevalent when
United States use of the racemic drug was discontinued
(Williams, 1990).
CARCINOGENICITY AND MUTAGENICITY
DNA’s unique three-dimensional structure may interact with
certain compounds stereospecifically (e.g., as previously
detailed with cisplatin). Nucleoside analog chemotherapeutic
agents (clofarabine, cytarabine, fludarabine, gemcitabine, etc.)
intentionally imitate native nucleoside 2R,5R structure in order
to inhibit replication. Rats treated with (S)-N#-nitrosonornicotine, a tobacco-specific carcinogenic nitrosamine, generated
three to five times higher levels of metabolite-DNA adducts
than with (R)-N#-nitrosonornicotine in the esophagus, a known
site of tumorogenesis (Lao et al., 2007). Epoxide transformations, in particular, provide the opportunity for stereospecific carcinogenicity or mutagenicity. P450 enzymes
convert the dietary and respirable dust contaminant aflatoxin
B1 to aflatoxin B1-8,9-epoxide, the toxicant. Exo-aflatoxin B18,9-epoxide interacts with DNA (forming guanine adducts in
particular) and is least 500-fold more potent than the endostereoisomer (Fig. 7A) (Stewart et al., 1996). Similarly, P450
enzymes convert styrene to styrene 7,8-epoxide, also present in
two enantiomeric forms. The R(þ)-enantiomer is more
mutagenic than the S()-enantiomer in S. typhimurium
TA100 strains, with the racemic mixture intermediate between
the two (Pagano et al., 1982). R(þ)-styrene 7,8-epoxide
depletes glutathione to a greater extent than S-styrene oxide
(Carlson et al., 2006). Benzo[a]pyrene, a polycyclic aromatic
hydrocarbon implicated in tumorogenesis, is stereospecifically
metabolized by cytochrome P450 to the reactive ultimate
toxicant (þ)-7R,8S-dihydrodiol-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, which subsequently reacts to primarily
form (þ)-trans-guanine adducts (Mocquet et al., 2007).
Nucleotide excision repair of the induced DNA lesions is also
carried out in a stereospecific manner. 1,3-Butadiene is
metabolized by P450 2E1 to butadiene monoepoxide, and
subsequently undergoes epoxidation and epoxide hydrolysis to
generate (R,R)- or (S,S)-butadiene diolepoxide isomers. In an in
vivo bacterial expression system, the (R,R)-enantiomer induced
base pair A to G mutations exclusively, whereas adducts of the
(S,S)-enantiomer were exclusively A to C mutations (Carmical
16
SMITH
Thalidomide
FIG. 7. Examples of chiral carcinogens and teratogens. Isomers of (A)
aflatoxin B1-8,9-epoxide, (B) thalidomide, and (C) retinoic acid. Thalidomide
undergoes chiral inversion in humans.
et al., 2000). Cis- and trans-methyl epoxycinnamates (methyl
3-phenyl-2,3-epoxy-propanoates) display opposite propensities
for rat hepatic glutathione conjugation (cis- > > trans-) and
Ames test mutagenicity (trans- >> cis-) (Rietveld et al., 1988).
Thus, stereoisomers may produce unique mutations.
REPRODUCTIVE TOXICITY
Chiral factors are implicated in the actual teratogenic
mechanism of several compounds. Stereospecific maternal or
fetal enzymes, fetal receptors, or transplacental transport
mechanisms might all contribute to toxicity. Several examples
follow where stereospecific mechanisms of human teratogenicity are supported. Animal embryologic toxicity of compounds primarily considered to be environmental pollutants is
contained in a following section.
Thalidomide apparently works by tumor necrosis factoralpha inhibition, inhibition of angiogenesis, and other mechanisms. R(þ)-thalidomide was reported to be responsible for
sedative effects (Eriksson et al., 2000; Hoglund et al., 1998),
whereas S()-thalidomide and its derivatives were reported to
be teratogenic (Fig. 7B) (Blaschke et al., 1979; Heger et al.,
1994). It was further proposed that the thalidomide tragedy
could have been avoided if the single R(þ)-enantiomer had
been used. Irrespective of the fact that an earlier study in an
appropriate animal model demonstrated equivalent teratogenic
potential of both isomers, which was greater than the racemate
(Fabro et al., 1967), chiral inversion occurs with thalidomide
(Reist et al., 1998). Humans interconvert (S)- and (R)thalidomide enantiomers (Fig. 7B) rapidly with both oral and
intravenous dosing (Eriksson et al., 2001). Albumin, hydroxyl
ions, phosphate, and amino acids appear to mediate this effect
(Reist et al., 1998). Therefore, even if single enantiomers of
thalidomide were provided, the ensuing enantiomeric mixture
could contribute to toxicity (Agranat et al., 2002). Similar
inter-conversion has been demonstrated for thalidomide
analogues (e.g., lenalidomide, EM 12, CC-4047), although
certain substitutions can confer optical stability (Schmahl et al.,
1988; Teo et al., 2003; U.S. Food and Drug Administration,
2005; Yamada et al., 2006). On the basis of the animal study
demonstrating teratogenicity of both thalidomide isomers and
evidence of human chiral inversion, exposure to either
thalidomide enantiomer or unstable thalidomide derivatives
during the period of sensitivity (days 20–36 after conception;
Dencker and Eriksson, 1998) would risk fetal harm. Susceptibility might additionally be influenced by genetic polymorphisms which alter thalidomide metabolism (Ando et al.,
2002) in the maternal/fetal unit.
Retinoic Acids
Following a 1979 landmark report, oral isotretinoin
revolutionized the treatment of recalcitrant cystic and conglobate acne (Peck et al., 1979). Alitretinoin (9-cis retinoic acid
for topical treatment of cutaneous Kaposi’s sarcoma lesions)
and isotretinoin (13-cis retinoic acid) are isomers of tretinoin
(all-trans retinoic acid) (Fig. 7C). Teratogenic effects are
presumed to be mediated in part via transformation of
alitretinoin and isotretinoin to all-trans retinoic acid (Adams,
1993). Variations in teratogenicity among the isomers also
likely arise secondary to species-specific, stereoselective tissue
transport (Collins and Mao, 1999). Cis-isomerization of the
retinoic acid side chain reduces the teratogenicity (Collins and
Mao, 1999). However, transplacental exposures of therapeutic
doses of isotretinoin were sufficient to produce well described,
severe teratogenic effects—including spontaneous abortion;
craniofacial, cardiac, thymic, and CNS malformations; motor
and sensory deficiencies; and sex-susceptible cognitive impairment (Lammer et al., 1985; McCaffery et al., 2003). Persistent
17
CHIRAL TOXICOLOGY
fetal exposures led to the creation of one of the most stringent
risk management prescribing programs in the United States
(iPLEDGE) (Honein et al., 2007). Excess exogenous retinoids
disrupt the precise retinoic acid concentrations at specific
stages of embryonic development which are required for
induction of anterior-posterior development of the brain,
dorsal-ventral development of the spinal cord, and some sexual
dimorphic traits (McCaffery et al., 2003). Structure does confer
receptor specificity—retinoic acid receptors (RARs) bind both
all-trans and 9-cis retinoic acid, whereas only 9-cis retinoic
acid binds to retinoid X receptors, which partner with RARs,
vitamin D receptors, thyroid hormone receptors, peroxisome
proliferator–activated receptors, and others (Germain et al.,
2006a, b). The low (1–2%) percutaneous absorption of topical
0.05% tretinoin does not significantly increase systemic
retinoid plasma concentrations above the range of natural
endogenous levels (Thielitz and Gollnick, 2008). Although
isolated case reports suggested a link between topical tretinoin
exposure and fetal congenital abnormalities, several studies
(215:430, 106:389, and 94:133 case-controls), failed to detect
any effect (Jick et al., 1993; Loureiro et al., 2005; Shapiro
et al., 1997). The U.S. FDA pregnancy classification for topical
tretinoin (up to 0.1%) (category C), reflects this decreased
perceived risk compared with the oral formulation (category
X). While not U.S. FDA approved, systemic absorption of
topical isotretinoin gel (up to 0.1%) is negligible despite
repeated application (Thielitz and Gollnick, 2008). Although
formal studies are lacking, daily application of topical
alitretinoin gel (0.1%) (pregnancy category D) for up to 60
weeks did not yield detectable 9-cis-retinoic acid metabolites or
9-cis-retinoic acid plasma concentrations above those in
untreated healthy volunteers (Eisai, Inc., 2007). Factors
increasing dermal systemic absorption could alter teratogenic
potential of the topical formulations.
Valproic Acid
Fetal VPA syndrome produces a consistent facial phenotype,
systemic and orthopedic involvement, CNS dysfunction, and
altered physical growth and cognitive development. It is
thought to occur due to exposure at weeks 20–24 as the neural
tube is closing. VPA and its S-derivatives appear to inhibit
histone deacetylase, which leads to increased unfolding of
chromatin and increased gene expression (Eikel et al., 2006).
In particular, pattern-forming, homeobox A1 (Hoxa1) mRNA
is produced in excess and outside of the normal developmental
periods following VPA and 4-yn-VPA exposure (Stodgell
et al., 2006). The VPA metabolite R(þ)- and S()-enantiomers
of 2-n-propyl-4-pentenoic acid (4-en-VPA) and 2-n-propyl-4pentynoic acid (4-yn-VPA) significantly differ in teratogenicity
(Nau et al., 1991). Almost four times more teratogenic than
VPA, (S)-4-yn-VPA is 7.5 times more teratogenic than the (R)isomer, and 1.9 times more teratogenic than the racemate,
despite similar neurotoxicity (Hauck and Nau, 1992). Whole
embryo cultures confirmed that (S)-4-yn-VPA produced dose-
dependent dysmorphogenesis and embryo death in contrast to
(R)-4-yn-VPA (Andrews et al., 1995).
ENVIRONMENTAL TOXICOLOGY
Many environmental contaminants are chiral, including
organophosphorus compounds, organochlorines, pyrethroids,
PCBs, polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), fipronil, and pharmaceutical contaminants. Degradation of these compounds, as well as
compound bioaccumulation, persistence, and toxicity often
show chiral dependence.
Organophosphorus Compounds
If the three substituent atoms are different, then the
phosphorous atom is a chiral center (Fig. 8A). In geographically distinct areas, enantioselective degradation of
organophosphorus compounds occurs (Lewis et al., 1999).
FIG. 8. (A) Enantiomers of substituted organophosphorus compounds
(X 6¼ Y 6¼ Z). (B) Chiral centers of the pyrethroids permethrin, cypermethrin,
cyfluthrin, and bifenthrin—the asterix (*) denotes chiral atoms. If the R1 and R2
substituents differ (e.g., in bifenthrin), then additional E- and Z-isomers are
possible. If R3 contains a nonhydrogen substituent group such as CN, an
alternative chiral carbon (#) is present. (C) PCB 139 (2,2#,3,4,4#,6hexachlorobiphenyl)—one of several PCBs with stable atropisomers which
have stereospecific effects in vivo. PCB atropisomers have generally been
identified on the basis of optical activity, as assignment of absolute
configuration is difficult.
18
SMITH
Some bacteria contain phosphotriesterases capable of catalyzing the cleavage of the phosphate-oxygen bond and degrading
the toxic organophosphate esters. Differences in geography,
temperature, and deforestation can cause these bacteria to
switch which enantiomer is preferentially degraded (Lewis
et al., 1999; Wong, 2006). As might be anticipated from the
previous discussion of acetylcholinesterase stereoselectivity in
relation to physostigmine, significant enantiomer- and speciesspecific acetylcholinesterase susceptibility has been demonstrated for several organophosphorus insecticides. This occurs
in such diverse species as Daphnia magna (water flea, the
standard model of environmental toxicity), the electric eel, and
humans (Nillos et al., 2007; Zhou et al., 2007). Therefore,
chirality is an important aspect in ascertaining the environmental impact of organophosphorus compounds.
The stereospecificity seen in organophosphorus insecticides
extends to chemical warfare nerve agents. Certain enantiomers are significantly more toxic, and show prolonged
in vivo persistence due to variable stereospecific protein
binding (Yeung et al., 2008). Variable acetylcholinesterase
inhibition has been demonstrated for tabun, sarin, soman
(with two chiral centers), and VX (Benschop and De Jong,
1988). These stereospecific differences might be anticipated
given selectivity of the active site previously described for
carbamates.
Pyrethroids
The pyrethroids, sodium channel opener insecticides derived
from chrysanthemum flowers, have at least 2 chiral centers.
Those with cyano-substitution at the a-carbon may have an
additional chiral center (Fig. 8B). This generates 4 or 8 possible
stereoisomers. Pyrethroids may isomerize slowly at the
asymmetric a-carbon atom in polar solvents and in the
presence of light (Wong, 2006). The trans-diastereomers of
b-cypermethrin and b-cyfluthrin are selectively degraded in
alkaline soils (Li et al., 2008). Pesticide-degrading bacteria
selectively metabolize cis-bifenthrin and permethrin (Liu
et al., 2005a). In geographically distinct separate soil samples,
enantioselective microbial-mediated degradation was frequently observed for cis-bifenthrin, permethrin, and cyfluthrin; the rate was dependent upon variations in the microbial
content, soil type, pH, and environmental conditions (Qin
et al., 2006). Stereospecific toxicity has been observed for the
pyrethroids. The (1R)-isomers of cycloprothrin were significantly more larvacidal than the (1S) enantiomers (Jiang et al.,
2008). The two enantiomers of cis-bifenthrin and permethrin
with the (1R) configuration, that is, (1R)-cis and (1R)-trans,
were substantially more toxic to ‘‘bystander’’ water fleas
(Ceriodaphnia dubia and Daphnia magna, an important food
sources for many larger aquatic organisms) (Liu et al.,
2005b). Only two of the eight cypermethrin and cyfluthrin
enantiomers, (1R)-cis-alpha-S and 1R-trans-alpha-S, had
significant activity, with 10–100 times more toxicity. Levolambda-cyhalothrin was over 162 times more acutely toxic
than dextro-lambda-cyhalothrin to zebrafish (Xu et al.,
2008a). It was also more embryocidal and teratogenic. Cispermethrin exposed mice had significant reproductive toxicity
including reduced epididymal sperm counts and motility, and
a decrease in testes and plasma testosterone levels not seen
with the trans-isomer, which appeared to have faster
metabolism (Zhang et al., 2008). Preliminary data also
suggests that (1S)-cis-bifenthrin is a much more significant
estrogen disruptor than the (1R)-enantiomer. (Wang et al.,
2007).
Polychlorinated Biphenyls, Dioxins, Dibenzofurans, and
Organochlorines
PCBs were used as coolants and lubricants in transformers,
capacitors, and other electrical equipment. Although U.S.
domestic production was banned in 1977, they remain present
in numerous hazardous waste sites. In humans, exposure to
PCBs has been linked to chloracne, ocular and pulmonary
symptoms in adults, neurobehavioral and immunological
changes in children, teratogenicity, and hepatic carcinoma
(Aoki, 2001). Additional thymic, CNS, and reproductive
toxicities exist in animals (Aoki, 2001;Tanabe, 1988). The
209 theoretical PCB cogeners are named and numbered
sequentially according to a variety of sources: IUPAC
nomenclature, Chemical Abstracts Service number, and the
original Ballschmiter and Zell enumeration as modified by
several authors (Mills et al., 2007). Seventy-eight PCBs
demonstrate axis chirality (existing as rotational nonsuperimposable isomers); 19 are stable atropisomers in biota (Fig. 8C)
(Haglund, 1996). Several PCB atropisomers display enantiospecific P450 enzyme interactions (detailed in Haglund, 1996;
Kania-Korwel et al., 2008). PCBs also demonstrate speciesspecific accumulation—for example, in pelicans, seals, and
polar bears (Karasek et al., 2007; Wiberg et al., 1998).
Furthermore, metabolite fractions are different from the
original food-source, indicating enantio-selective formation,
metabolism, transport, or clearance. Moreover, tissue-specific
and organ-specific enantiomer-selective retention has been
shown in rats. Compared with adipose and liver tissue, rat
lung tissues had reversed enantiomer preferences for PCB 149
metabolites (Larsson et al., 2002). Enrichment of specific
PCB 95, PCB 149, and PCB 132 isomers is reported in human
liver samples (Chu et al., 2003). The concentration of at least
five relevant PCB congeners are enriched in milk and dairy
products from cows, goats, and ewes in a dairy-product and
species-specific manner (Bordajandi and Gonzalez, 2008).
This is presumed to occur through species-dependent
metabolism as well as further transformations by microorganisms during the fermentation and ripening process.
Lastly, levo-PCB 136 was recently shown to enantioselectively enhance ryanodine binding at ryanodine type 1 and 2
receptors and increase calcium flux, raising the possibility that
chiral PCBs may have additional toxicological mechanisms
(Pessah et al., 2009).
CHIRAL TOXICOLOGY
In addition to the multiple PCB isomers, 456 of 837 possible
methylsulfonyl-PCB-derivatives are chiral (Nezel et al., 1997).
The mercapturic acid pathway forms methyl sulfone metabolic
products of PCBs (MeSO2-CB) (Karasek et al., 2007).
Microbial reductive dechlorination—the major degradation
mechanism for PCBs under anaerobic conditions—occurs in
an enantiospecific manner for certain PCBs (e.g., PCB 91 and
PCB 95) (Pakdeesusuk et al., 2003). Examining the specific
isomers thus helps elucidate the contribution of biological
activity (natural attenuation) versus chemical, distribution, and
transport processes in contaminated ecosystems (Nezel et al.,
1997). Although atmospheric PCB contributions are racemic,
certain PCBs are nonracemic in water, suspended particulate
matter, sediments and phytoplankton (which absorb PCBs by
passive diffusion and lack the ability to metabolize them
[Asher et al., 2007]). As discharge of water from a previously
contaminated upstream source increased, the enantiomer
fraction of PCBs was obtained down-stream diverged from
the racemate, leading to the identification of transport of
contaminated sediment as the major PCB source. Thus, the
concept of chiral fingerprinting or ‘‘chiral signatures’’ of PCBs
can now being applied to differentiate among PCBs source
contamination from upstream river-water, storm-water runoff,
sewer overflows, and atmospheric deposition from urbangenerated PCBs (Asher et al., 2007).
As early as 1969 it was noted that the stereoisomers of
cyclodiene insecticides could produce different toxicity. Mice
fed endrin at 5 ppm suffered a 33% mortality, whereas
dieldrin (its stereoisomer) was no different than control (Good
and Ware, 1969). Both compounds reduced the litter size of
offspring. Similar to the multiple PCB congeners, PCDD
molecules can exist in 75 possible planar isomers. Isomer
toxicity varies greatly by factors of 1000 to 10,000 (Boening,
1998). Isomeric analysis of agricultural soils permits source
determination of PCDDs and PCDFs (municipal incinerators
versus agrochemical impurities) (Xu et al., 2008b). Depending on soil type and location, preferential degradation of
either enantiomer of o,p#-DDT may occur (Aigner et al.,
1998; Li et al., 2006). The ()-o,p#-DDT enantiomer is an
active estrogen mimic at the human estrogen receptor,
whereas (þ)-o,p#-DDT was negligible (Hoekstra et al.,
2001). Thus, the environmental impact of organochlorines
must be approached from a geo-local, species-specific, and
organ-specific perspective.
Fipronil
Fipronil, a racemic phenylpyrazole pesticide, is a noncompetitive GABA receptor antagonist available in the United
States since 1996. Humans exposed to fipronil may have
headache, nausea, and seizures, and prolonged GABAA
receptor blockade has been demonstrated in mammalian brains
(Li and Akk, 2008). Fipronil is also used in commercial pet
products. Fipronil’s environmental fate is sediment-dependent:
preferential transformation of S(þ)-fipronil occurs in anoxic
19
sulfidogenic sediment, whereas preferential transformation of
R()-enantiomer in methanogenic anoxic sediment (Jones
et al., 2007). In a geographically disparate area, under flooded
(anaerobic) conditions, (S)-fipronil was preferentially degraded
in methanogenic soil samples, whereas no selectivity was noted
under aerobic conditions, a difference attributed to alternative
pH, temperature, soil water content, organic matter content or
microbial populations (Tan et al., 2008). Determination of the
persistent enantiomer is important to assess environmental risk.
Although highly selective to insect nerve cells, ‘‘aquatic
bystanders’’ are susceptible to species-specific enantiomer
toxicity of fipronil. C. dubia is selective affected by the (S)enantiomer (Wilson et al., 2008). Similarly, crayfish are
significantly more sensitive to the (S)-enantiomer, whereas
larval grass shrimp are significantly more sensitive to the (R)enantiomer (Overmyer et al., 2007). Highlighting the economic
importance of understanding these complex enantiomer
relationships, the introduction of rice seed treated with fipronil
produced major losses in Louisiana crayfish harvests, and
degradation products were found to persist for several years
(Bedient et al., 2005). Fipronil is rapidly biotransformed by the
rainbow trout, which selectively transform the (S)-enantiomer.
The sulfone metabolite has a thrice-greater half-life and thus
may bioaccumulate (Konwick et al., 2006). Future environmental assessment of fipronil will have to account for
local conditions, enantio-selective food-source toxicity, and
bioaccumulation.
Pharmaceutical Contaminants
Pharmaceuticals may contaminate the environment following unchanged parent compound elimination from humans or
animals or active disposal in solid or liquid waste streams.
Pharmaceutical residues persist nearly year round in some
major waterways (Comeau et al., 2008; Sacher et al., 2008).
However, relatively little work has been done on chiral aspects
of these xenobiotics or their significance. The NSAIDs and
ibuprofen in particular can be found in many rivers and lakes;
the active (S)-enantiomer was preferentially degraded in lake
water (Buser et al., 1999). Nonpharmacologically active R()ibuprofen was degraded more rapidly by microorganisms in
biofilm reactors than the pharmacologically active isomer
(Winkler et al., 2001). In aquatic toxicity studies, growth and
feeding of P. promelas (fathead minnow) were more adversely
affected by S-fluoxetine than R-fluoxetine, whereas water fleas
did not have stereospecific susceptibility (Stanley et al., 2007).
The enantiomeric fraction of R(þ)-propranolol decreases
following wastewater treatment, and thus water samples which
contained racemic mixtures of propranolol confirmed suspected
discharges of untreated sewage (Fono and Sedlak, 2005).
Similar studies have examined atenolol and metoprolol isomers
of wastewater effluent (Nikolai et al., 2006). (R)-propranolol
has greater effects on reproduction than either the racemate or
the (S)-isomer at the highest tested dose in water fleas, whereas
growth was affected more by (S)-propranolol in P. promelas,
20
SMITH
similar to mammals (Stanley et al., 2006). Residues of 4methylbenzylidene camphor, an organic ultraviolet filter used
in personal care sunscreens products, could be modified by
enantioselective biodegradation and in lakes and in fish (Buser
et al., 2005).
FORENSIC TOXICOLOGY
In forensics, chiral principles can be applied to both to drug/
product seizures and to biological samples. It has been
estimated that over half of illicit compounds possess at least
one chiral center (Mile, 2005). Truxilline, a tropine alkaloid, is
present as 11 stereoisomers in the coca leaf. Resolution of these
and other stereoisomers of cocaine-associated impurities can
provide a manufacturing fingerprint for law-enforcement
intelligence and strategic purposes (Tagliaro et al., 2007).
Illicitly produced heroin is commonly ‘‘cut’’ with sugars; thus,
the chiral analysis of these in addition to other excipients
(phenacetin, caffeine, etc.) may provide important information
for forensic purposes (Lurie, 1998; United Nations Office on
Drugs and Crime, 2005). Chiral analysis can be applied to
other drug seizures. For example, presumed methamphetamine
seizures might demonstrate levo-ephedrine and dextromethamphetamine, which would be consistent with levo-ephedrine
as the precursor material. Such analysis can be extended to
other phenylethylamine derivatives such as ‘‘ecstasy’’ (commonly 3,4-methylenedioxymethamphetamine) and N,N-dimethylamphetamine to provide clues to precursor materials and
synthesis pathways (Lee et al., 2007; Tagliaro and Bortolotti,
2008). Due to the very different U.S. DEA scheduling of
racemic methorphan (CII, not clinically available in the United
States), levomethorphan (CII, not clinically available in the
United States) and dextromethorphan (unscheduled), forensic
determination of methorphan isomers seizures must be
performed in order to support illegality (Lurie and Cox, 2005).
Chiral principles must be applied to correctly interpret the
significance of ‘‘positive’’ biological samples from employment or post-mortem drug testing. As an example, certain
amphetamine or methamphetamine enantiomer compositions
may or may not be appropriate following a reported history of
ingestion (Fig. 9). Methamphetamine is metabolized unidirectionally to amphetamine (and 4-hydroxymethamphetamine)
(Jirovsky et al., 1998). d-Methamphetamine is metabolized
more rapidly than the l-enantiomer; thus, the enantiomer ratio
will change over time (Cody, 2002). Pharmacodynamic
differences include induction of higher systolic blood pressures
and more prolonged and psychologically desirable effects with
the d-isomer (Mendelson et al., 2006). Finding methamphetamine would undermine a claim of medical legitimacy in
xenobiotics composed of or directly metabolized to amphetamine—for example, one would expect to find a mixture of
d-and l-amphetamine, but not methamphetamine in individuals
consuming Adderall [d,l-amphetamine salts (3:1), DEA
schedule II] (Barr Laboratories, 2007). Similarly, Dexedrine
(dextroamphetamine sulfate, DEA schedule II) should only
result in serum concentrations of d-amphetamine, and only
d-amphetamine should be detected following ingestion of
Vyvanse (lisdexamfetamine dimesylate, DEA schedule II),
a dextroamphetamine pro-drug (Fig. 9). Vicks Vapor Inhaler
(unscheduled) contains 50 mg of l-methamphetamine (per
inhaler). Forensic specimens should contain only the l-isomer
and the l-amphetamine metabolite. Conversely, Desoxyn
(d-(S)-methamphetamine hydrochloride, DEA schedule II)—
prescribed for attention deficit disorder with hyperactivity and
exogenous obesity—should yield solely the d-isomers. Didrex
(d-benzphetamine, DEA schedule III) is an anti-obesity drug
marketed in the United States. Metabolism to d-methamphetamine and separate metabolism to d-amphetamine result in
much higher d-amphetamine to d-methamphetamine ratios
(mean ¼ 2.4) than normally seen in methamphetamine abuse
(without generation of l-isomers) (Cody, 2002). Eldepryl
(selegiline hydrochloride, unscheduled), used in the treatment
of Parkinson’s disease, is manufactured only as the l-isomer. A
certain percentage is metabolized to (only) l-methamphetamine
and l-amphetamine. Clobenzorex is an anorexic drug now
illegal in US, but abused in professional sports. It is available
abroad (as Asenlix, Dinintel, and Finedal) as part of unapproved diet regimens utilized by U.S. residents (U.S. Food
and Drug Administration, 1987). Approximately 5% is
converted to racemic amphetamine (Baden et al., 1999).
Fenproporex (DEA schedule IV) is appetite suppressant used
outside U.S. FDA action occurred in 2006 because the
‘‘Brazilian Diet Pill’’ contained this compound and resulted
in workplace drug testing ‘‘failures’’ (U.S. Food and Drug
Administration, 2006). Roughly 25–35% is converted to
racemic amphetamine. Methamphetamine and amphetamine
metabolites of mefenorex (CIV), another anorectic marketed
primarily in Europe, may persist beyond the parent compound
(Engel et al., 1986; Musshoff, 2000). Gewodin is an over the
counter antipyretic/analgesic multi-ingredient product available
in Germany, Taiwan, and elsewhere, containing acetaminophen, propyphenazone (isopropylphenazone), caffeine, and
famprofazone (Musshoff and Kraemer, 1998). Stereoselective
famprofazone metabolism leads to significantly more
l-methamphetamine production than l-amphetamine or the
d-isomers (Rodriguez et al., 2004). With wide interindividual
variability, the calcium channel antagonist and anti-anginal
prenylamine (unscheduled) metabolizes to significantly more
d-metabolites (and d-amphetamine) than l-amphetamine
(Kraemer et al., 2003; Liu and Liu, 2002). Amphecloral
(INN: amfecloral) is a phenethylamine derivative which was
patented in 1960 as an amphetamine pro-drug with prolonged
duration of action (Cavallito, 1960; Kolliker and Oehme,
2004). Metabolism yields chloral hydrate plus d-amphetamine
or d,l-amphetamine, depending on the method of preparation
(Fig. 9). Other compounds which metabolize to methamphetamine or amphetamine include amphetaminil (unscheduled),
CHIRAL TOXICOLOGY
21
FIG. 9. Pharmaceuticals that contain or are metabolized to amphetamine isomers and methamphetamine isomers. Solid lines indicate that no metabolism is
required; dotted lines indicate that metabolism occurs. Amphecloral, clobenzorex, fenproporex, and prenylamine are metabolized to both d-(S)- and l-(R)amphetamine.
dimethylamphetamine (CI), ethylamphetamine (CI), fencamine
(unscheduled), fenethylline (CI), furfenorex (unscheduled), and
mesocarb (unscheduled) (Cody, 2002; Liu and Liu, 2002;
Musshoff, 2000). Thus, a detailed history of reported
xenobiotic ingestion and appropriate isomer analysis may
support or refute a claim of legitimate pharmaceutical ingestion
or aid in the determination of cause of death.
Chiral analysis has been applied to screen athletes for
exogenous administration of androgens since 1983 (Bowers,
2008). The endogenous steroid profile of testosterone (T) to its
enantiomer epitestosterone (E)—the urinary T/E ratio—occurs
in populations in two modal distributions in both sexes at about
0.1 and 1.0 (Bowers, 2008). Rare cases of physiologically high
T/E ratios (between 6 and 12) and low T/E ratios (due to
deletion polymorphism in the uridine diphospho-glucuronosyl
transferase 2B17 gene) are reported (Dehennin, 1994; Schulze
et al., 2008). According to the rules of the World Anti-Doping
Agency, an E/T glucuronide ratio equal to or exceeding 4 to 1
is an atypical result suggestive of exogenous androgenic
steroid administration and requires further investigation (World
22
SMITH
Anti-Doping Agency, 2007). T/E ratios can be coupled with
evaluation of 13C/12C ratios (as pharmaceutically produced
anabolic steroids exhibit a depleted ratio on account of their
plant origin) to provide additional evidence of a doping offense
(Piper et al., 2008).
CONCLUSION
Chiral considerations are relevant to diverse aspects of
toxicology and pharmacology. The additional complexity
permits a more complete and precise understanding of
toxicological pathophysiology. Evaluation of chiral compounds must take into account three-dimensional structureactivity relationships, which may take on varied importance at
different receptor types. Local conditions species and tissue
differences and population polymorphisms may additionally
influence enantiomer ratios and xenobiotic effects.
ACKNOWLEDGMENTS
This manuscript was developed from a presentation at the
American College of Medical Toxicology Spring Conference,
San Diego, CA, USA, March 2008. The author is indebted to
Lewis S. Nelson, MD, FACEP, FACMT, and Mary Ann
Howland, PharmD, DABAT, FAACT for their insightful
suggestions and manuscript review.
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