Non-cytochrome P450-mediated bioactivation and its toxicological relevance.
The bioactivation of drugs is often associated with toxicological outcomes; however, for most cases, the causal relationship between bioactivation and toxicity is not well established despite extensive research that attempts to elucidate the mechanisms leading to the formation of chemically reactive species, presumably the initial step towards adverse reactions. Due to rapid advancement in the research of cytochrome P450s (CYPs) and the prevalence of CYP involvement in the metabolic clearance of pharmaceuticals, CYP-mediated bioactivation is widely investigated and reviewed, while non-CYP-mediated bioactivation has not been emphasized. The widespread use of metabolic stability screening in drug discovery, however, has led to the identification of new chemical entities that rely on non-CYP enzymes for clearance, and the number of drugs that undergo metabolism via these enzymes has increased. Non-CYP enzymes can be divided into four general categories according to their enzymatic function, namely, oxidative, reductive, conjugative and hydrolytic. The aim of this review is to complement the existing literature on CYP-mediated metabolism by focusing on bioactivation mediated non-CYP enzymes and provide representative examples in each category.
['Gan|Jinping|J|', 'Ma|Shuguang|S|', 'Zhang|Donglu|D|']
D000818:Animals D001711:Biotransformation D003577:Cytochrome P-450 Enzyme System D064420:Drug-Related Side Effects and Adverse Reactions D006801:Humans D006868:Hydrolysis D050217:Metabolic Detoxication, Phase II D010084:Oxidation-Reduction D004364:Pharmaceutical Preparations
non-CYP enzymes Drug bioactivation conjugation reactions hydrolytic reactions reductive reactions