ToxSci Advance Access published online on May 4, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp097
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Chiral Toxicology: It's the Same Thing...Only Different
* New York University School of Medicine, New York, NY, USA
New York City Poison Control Center, New York, NY, USA
Corresponding author: Silas W. Smith, MD, Corresponding author address: Department of Emergency Medicine, Bellevue Hospital Center, 462 First Avenue, Room A-345A, New York, NY 10016 USA, Telephone: (212) 447-3395, Fax: (212) 447-8223, Email: Silas.Smith{at}nyumc.org
Received February 18, 2009; revision received April 5, 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.