Production of chlorzoxazone glucuronides via cytochrome P4502E1 dependent and independent pathways in human hepatocytes

Archives of Toxicology
Nicolas QuesnotPascal Loyer

Abstract

CYP2E1 activity is measured in vitro and in vivo via hydroxylation of the Chlorzoxazone (CHZ) producing the 6-hydroxychlorzoxazone (OH-CHZ) further metabolized as a glucuronide excreted in urine. Thus, the quantification of the OH-CHZ following enzymatic hydrolysis of CHZ-derived glucuronide appears to be a reliable assay to measure the CYP2E1 activity without direct detection of this glucuronide. However, OH-CHZ hydrolyzed from urinary glucuronide accounts for less than 80% of the CHZ administrated dose in humans leading to postulate the production of other unidentified metabolites. Moreover, the Uridine 5'-diphospho-glucuronosyltransferase (UGT) involved in the hepatic glucuronidation of OH-CHZ has not yet been identified. In this study, we used recombinant HepG2 cells expressing CYP2E1, metabolically competent HepaRG cells, primary hepatocytes and precision-cut human liver slices to identify metabolites of CHZ (300 μM) by high pressure liquid chromatography-UV and liquid-chromatography-mass spectrometry analyses. Herein, we report the detection of the CHZ-O-glucuronide (CHZ-O-Glc) derived from OH-CHZ in culture media but also in mouse and human urine and we identified a novel CHZ metabolite, the CHZ-N-glucuronide (CHZ-N-Glc)...Continue Reading

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Citations

Mar 3, 2019·Journal of Cellular Biochemistry·Aki KawanoToshinori Okinaga
Apr 14, 2020·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Chloé HugbartThomas Gicquel
Nov 18, 2020·Scientific Reports·Brendan Le DaréThomas Gicquel
Apr 20, 2021·Toxicology Letters·Brendan Le DaréThomas Gicquel
Nov 10, 2020·Toxicology in Vitro : an International Journal Published in Association with BIBRA·D DesaulniersC Parfett

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Methods Mentioned

BETA
acetylation
biopsies
PCR

Software Mentioned

Prismsoftware
Xcalibur
GraphPad

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