Glucuronidation of SN‐38 serves as an important metabolic pathway in determining the toxic effects of irinotecan. The role of UDP‐glucuronosyltransferases (UGT) 1A9 in SN‐38 glucuronidation pathway is very confusing. This study re‐investigates the pathway through testing effects of bovine serum albumin (BSA) and the selective inhibitor on SN‐38 glucuronidation in pooled human liver microsomes (HLM) and recombinant UGT1A1/UGT1A9. For UGT1A1, SN‐38 glucuronidation was little affected by BSA. Whether in the presence of BSA or not, the reactions both obey Michaelis–Menten kinetics with closed Vmax/Km values. For UGT1A9 and HLM, BSA can significantly accelerate SN‐38 glucuronidation activities and similar effects are further observed on kinetic patterns. In the absence of BSA, reactions by HLM and UGT1A9 both display substrate inhibition kinetics. When BSA is included in the incubations, the reactions exhibit Michaelis–Menten kinetics. To get the true contribution of UGT1A9 in SN‐38 glucuronidation, a relative activity factor (RAF) approach was additionally used. It is suggested that UGT1A9 and 1A1 contribute equally to SN‐38 glucuronidation in HLM. Furthermore, in the presence of BSA, magnolol, a selective UGT1A9 inhibitor, displays moderate inhibition against HLM. Results together conclude that UGT1A9 serves as an additional important contributor to hepatic SN‐38 glucuronidation.
Basic and Clinical Pharmacology & Toxicology – Wiley
Published: Jan 1, 2018
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