ToxSci Advance Access originally published online on May 4, 2009
Toxicological Sciences 2009 110(1):4-30; doi:10.1093/toxsci/kfp097
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Chiral Toxicology: It's the Same Thing...Only Different
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* New York University School of Medicine, New York, New York 10016
New York City Poison Control Center, New York, New York 10016
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: Silas.Smith{at}nyumc.org.
Received February 18, 2009; accepted April 29, 2009
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Abstract |
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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.
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.