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Current Topics in Virology   Volumes    Volume 4 
HIV-1 Tat induced alterations in oxidation-reduction potential as a model to extend the understanding of drug idiosyncrasy
David F. Lehman, Michael J. Rieder, Daria LaRocca, Peter D. Holohan
Pages: 89 - 95
Number of pages: 7
Current Topics in Virology
Volume 4 

Copyright © 2004 Research Trends. All rights reserved

Despite accounting for a minority of adverse drug events, idiosyncratic reactions are responsible for a disproportionate degree of patient morbidity. The biological mechanisms underlying idiosyncrasy likely involve immunological responses to reactive intermediates of culprit drug metabolism.

Specifically, idiosyncratic toxicity from sulfonamide antimicrobials is initiated by its [nitroso] reactive intermediate, an auto-oxidized form of its immediate precursor, sulfamethoxazole hydroxylamine. An oxidizing environment favors the [nitroso] form in this equilibrium. We linked viral replication with the propensity to develop idiosyncratic reactions from sulfonamides in AIDS patients and hypothesized that this effect is from the intese oxidizing environment produced by HIV-1 Tat. Subsequent observations showed a dose-dependent relationship between HIV-1 Tat, reduced glutathione, and sulfamethoxazole toxicity as expressed via peripheral blood mononuclear cell lysis.

Observations in HIV disease may provide the clarity to formulate a broader working model concerning idiosyncratic drug toxicity in the general population. According to this model, drug idiosyncrasy occurs at the overlap between the genetic expression of drug metabolizing enzymes, other as yet unidentified enzymes, and a state of oxidative stress. The characteristics of this model and supporting evidence for its validity are discussed.

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