Biosynthesis of imipramine glucuronide and characterization of imipramine glucuronidation catalyzed by recombinant UGT1A4

Acta Pharmacologica Sinica
Mingrong Qian, Su Zeng

Abstract

To study the profile of imipramine N+-glucuronidation using homogenates of recombinant uridine-5'-diphosphoglucuronosyltransferase 1A4 (UGT1A4) from baculovirus-infected sf9 cells. Recombinant UGT1A4 was obtained from sf9 cells infected with recombinant baculovirus. Imipramine N(+)-glucuronide was biosynthesized by incubating imipramine with recombinant UGT1A4 and then purified with solid-phase cartridges. A reversed phase-high pressure liquid chromatography (RP-HPLC) assay method was used to directly measure the concentration of imipramine and its metabolite, imipramine N(+)-glucuronide, with p-nitrophenol as the internal standard. The validated method was used to characterize the activity of recombinant UGT1A4 and carry out kinetic studies on imipramine glucuronidation in vitro. The high concentration of imipramine inhibited glucuronide conjugation, so the formula V=V(max).S/(Km+S+S(2)/K(i)) was used to calculate the parameters, using MATLAB software. The values of apparent K(m), K(i), and V(max) for imipramine glucuronidation via UGT1A4 were 1.39+/-0.09 mmol/L, 6.24+/-0.45 mmol/L and 453.81+/-32.12 pmol/min per mg cell homogenate (n=3), respectively. As a specific substrate of UGT1A4, imipramine was used as a convenient meth...Continue Reading

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Jun 5, 2004·Biochemical and Biophysical Research Communications·Mingrong QianSu Zeng
Feb 15, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Asami MoriYoshihiro Takeuchi

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Citations

Mar 8, 2017·Drug Metabolism Reviews·Guangyi YangMing Hu
Jan 10, 2017·Chembiochem : a European Journal of Chemical Biology·Ryan R HughesJon S Thorson
Feb 13, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ryoichi FujiwaraTsuyoshi Yokoi

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