Glucuronidation of capsaicin by liver microsomes and expressed UGT enzymes: reaction kinetics, contribution of individual enzymes and marked species differences

Objective: The objectives of this study are to characterize capsaicin glucuronidation using liver microsomes and to determine the contribution of individual UDP-glucuronosyltransferase (UGT) enzymes to hepatic glucuronidation of capsaicin.Methods: The rates of glucuronidation were determined by incubating capsaicin with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by model fitting. Determination of the relative activity factors, expression-activity correlation and activity correlation analysis were performed to identify the main UGT enzymes contributing to capsaicin metabolism.Results: Capsaicin was efficiently glucuronidated in pooled human liver microsomes (pHLM). UGT1A1, 1A9 and 2B7 (as well as the gastrointestinal enzymes UGT1A7 and 1A8) showed considerable activities. Capsaicin glucuronidation was significantly correlated with 3-O-glucuronidation of β-estradiol (r = 0.637; p = 0.014) and with UGT1A1 protein levels (r = 0.616; p = 0.019) in a bank of individual HLMs (n = 14). Also, capsaicin glucuronidation was strongly correlated with zidovudine glucuronidation (r = 0.765; p < 0.01) and with UGT2B7 protein levels (r = 0.721; p < 0.01). UGT1A1, 1A9 and 2B7 contributed 30.3, 6.0 and 49.0% of total glucuronidation of capsaicin in pHLM, respectively. Further, glucuronidation of capsaicin by liver microsomes showed marked species difference.Conclusion: Capsaicin was subjected to significant hepatic glucuronidation, wherein UGT1A1 and 2B7 were the main contributing enzymes.