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...

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Published inDrug metabolism reviews Vol. 48; no. 4; pp. 473 - 501
Main Authors Gan, Jinping, Ma, Shuguang, Zhang, Donglu
Format Journal Article
LanguageEnglish
Published England Taylor & Francis 01.11.2016
Subjects
Animals
Biotransformation
conjugation reactions
Cytochrome P-450 Enzyme System - metabolism
Drug bioactivation
Drug-Related Side Effects and Adverse Reactions
Humans
Hydrolysis
hydrolytic reactions
Metabolic Detoxication, Phase II
non-CYP enzymes
Oxidation-Reduction
Pharmaceutical Preparations - metabolism
reductive reactions
conjugation reactions
reductive reactions
hydrolytic reactions
non-CYP enzymes
Drug bioactivation
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Summary: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.
ISSN:0360-2532
1097-9883
DOI:10.1080/03602532.2016.1225756