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RESEARCH PRODUCT

Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs

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description

Almost all drugs are metabolized in the human organism. In most cases this changes the toxicity, sometimes by toxification, sometimes by detoxification. For obvious ethical reasons, the toxicity cannot be experimentally studied in human beings. In systems available for toxicity studies such as whole animals or human or animal cells in culture, the drug metabolism is substantially different from that in the human organism. Risk assessment for human therefore requires knowledge of drug metabolism, its differences between systems, and the consequences for toxicity. In phase 1 of drug metabolism (oxidoreductions and hydrolyses) drugs are often toxified. This is especially the case if the resulting metabolite is a reactive electrophile that covalently modifies nucleophilic substituents of key steering cellular macromolecules such as nucleic acids and proteins. Such reactive electrophilic metabolites include epoxides, α,β-unsaturated carbonyls, and reactive esters. Phase 2 reactions of drug metabolism (conjugations) are predominantly detoxifications. Predictable exceptions include the toxification of vicinal dihalogenated alkanes and of perchlorinated ethylene by the otherwise classical detoxifying enzymes glutathione S-transferases and the formation of the precursor of the most highly genotoxic and carcinogenic bay region diol-epoxides from angular polycyclic aromatic hydrocarbon-derived pre-bay epoxides by the otherwise classical detoxifying enzyme microsomal epoxide hydrolase. Such knowledge is essential for understanding, predicting, and correctly extrapolating drug metabolism-dependent toxicities.