Carbon–carbon bond cleavage and formation reactions in drug metabolism and the role of metabolic enzymes

Abstract

Elimination of xenobiotics from the human body is often facilitated by a transformation to highly water soluble and more ionizable molecules. In general, oxidation–reduction, hydrolysis, and conjugation reactions are common biotransformation reactions that are catalyzed by various metabolic enzymes including cytochrome P450s (CYPs), non-CYPs, and conjugative enzymes. Although carbon–carbon (C–C) bond formation and cleavage reactions are known to exist in plant secondary metabolism, these reactions are relatively rare in mammalian metabolism and are considered exceptions. However, various reactions such as demethylation, dealkylation, dearylation, reduction of alkyl chain, ring expansion, ring contraction, oxidative elimination of a nitrile through C–C bond cleavage, and dimerization, and glucuronidation through C–C bond formation have been reported for drug molecules. Carbon–carbon bond cleavage reactions for drug molecules are primarily catalyzed by CYP enzymes, dimerization is mediated by peroxidases, and C-glucuronidation is catalyzed by UGT1A9. This review provides an overview of C–C bond cleavage and formation reactions in drug metabolism and the metabolic enzymes associated with these reactions.