Cyp3a11‐mediated testosterone‐6β‐hydroxylation decreased, while UGT1a9‐mediated propofolO‐glucuronidation increased, in mice with diabetes mellitus

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Abstract
Thedb/dbmouse is one of the most popular animal models for type 2 diabetes mellitus, but changes in the activities of important P450s and UGTs are still not completely clear. This study was designed to investigate the alterations of major hepatic cytochrome P450s and UDP‐glucuronyltransferase enzymes indb/dbmice. Mouse liver microsomes (MLMs) were obtained from maledb/dbmice and their wild type littermates. After incubation of the substrates separately with MLMs, the samples were pooled and analysed by high‐throughput liquid chromatography–tandem mass spectrometry system for the simultaneous study of nine phase I metabolic reactions and three glucuronidation conjugation reactions to determine the activity of the metabolic enzymes. Compared with normal controls, theClintestimate for testosterone‐6β‐hydroxylation was lower (46%) (p < 0.05), while theVmaxandClintestimates for propofolO‐glucuronidation were 5‐fold higher (p < 0.01) in the liver microsomes fromdb/dbmice. There was no significant difference in phase I metabolic reactions of phenacetin‐O‐deethylation, coumarin‐7‐hydroxylation, bupropion‐hydroxylation, omeprazole‐5‐hydroxylation, dextromethorphan‐O‐demethylation, tolbutamide‐4‐hydroxylation, chlorzoxazone‐6‐hydroxylation and midazolam‐1‐hydroxylation and in glucuronidation reactions of estradiol 3‐O‐glucuronidation, and 3‐azido‐3‐deoxythymidine glucuronidation. The data suggest that, indb/dbmice, the activity of Cyp3a11, catalysing testosterone‐6β‐hydroxylation, decreased, while the activity of UGT1a9, catalysing propofolO‐glucuronidation, increased. Copyright © 2016 John Wiley & Sons, Ltd.
Funding Information
  • ‘085’ First-Class Discipline Construction of Science and Technology Innovation (085ZY1205)
  • Program for Shanghai Innovative Research Team in University (2009)
  • National Natural Science Foundation of China (81303296 and 30873231)

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