Identification of human UDP-glucuronosyltransferases catalyzing hepatic 1α,25-dihydroxyvitamin D3 conjugation

作者: Takanori Hashizume , Yang Xu , Michael A. Mohutsky , Jeffrey Alberts , Chad Hadden

DOI: 10.1016/J.BCP.2007.11.008

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摘要: Abstract The biological effects of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 ) are terminated primarily by P450-dependent hydroxylation reactions. However, the hormone is also conjugated in liver and a metabolite, presumably glucuronide, undergoes enterohepatic cycling. In this study, identity human enzymes capable catalyzing 1,25(OH) glucuronidation reaction was investigated order to better understand environmental endogenous factors affecting disposition vitamin . Among 12 different UGT isozymes tested, only UGT1A4 ≫ 2B4 2B7 supported reaction. Two monoglucuronide metabolites were generated recombinant UGT1A4 microsomes. most abundant product identified mass spectral NMR analyses as 25- O -glucuronide isomer. formation Supersomes microsomes followed simple hyperbolic kinetics, yielding respective K m V max values 7.3 11.2 μM 33.7 ± 1.4 32.9 ± 1.9 pmol/min/mg protein. calculated intrinsic M1 clearance for 14-fold higher than next best isozyme, UGT2B7. There limited (four-fold) inter-liver variability -glucuronidation rate, but it highly correlated with relative rate second, minor metabolite. addition, both inhibited >80% selective inhibitor, hecogenin. If recycling represents significant component intestinal systemic disposition, monoglucuronides hepatic constitutes an important initial step.

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