Hepatic glucuronidation of 4-tert-octylphenol in humans: inter-individual variability and responsible UDP-glucuronosyltransferase isoforms

• Published in: Archives of toxicology Vol. 91; no. 11; pp. 3543 - 3550
• Main Authors: Isobe, Takashi, Ohkawara, Susumu, Tanaka-Kagawa, Toshiko, Jinno, Hideto, Hanioka, Nobumitsu
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2017; Springer Nature B.V
• Subjects: 4-tert-Octylphenol; Adolescent; Adult; Aged; Biomedical and Life Sciences; Biomedicine; Biphenyl Compounds - metabolism; Biphenyl Compounds - pharmacokinetics; Correlation analysis; Correlation coefficient; Correlation coefficients; Detoxification; Diclofenac; Diclofenac - pharmacokinetics; Endocrine disruptors; Endocrine Disruptors - pharmacokinetics; Environmental Health; Female; Glucuronides - metabolism; Glucuronosyltransferase; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Humans; Isoforms; Kinetics; Liver; Liver - drug effects; Liver - metabolism; Male; Microsomes; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Middle Aged; Nonsteroidal anti-inflammatory drugs; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Phenols - pharmacokinetics; Proteins; Reaction kinetics; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Toxicokinetics and Metabolism; UDP-glucuronosyltransferase; Variability; UDP-glucuronosyltransferase (UGT); Human liver microsome; Glucuronidation; Recombinant human UGT; 4; Octylphenol (4-tOP); 4-tert-Octylphenol (4-tOP)
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-017-1982-1

4- tert -Octylphenol (4-tOP) is an endocrine-disrupting chemical. It is mainly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in humans. The purpose of this study was to assess inter-individual variability in and the possible roles of UGT isoforms in hepatic 4-tOP glucuronidation in the humans. 4-tOP glucuronidation activities in the liver microsomes and recombinant UGTs of humans were assessed at broad substrate concentrations, and kinetics were analyzed. Correlation analyses between 4-tOP and diclofenac or 4-hydroxybiphenyl activities in pooled and individual human liver microsomes were also performed. Typical CL int values were 17.8 mL/min/mg protein for the low type, 25.2 mL/min/mg protein for the medium type, and 47.7 mL/min/mg protein for the high type. Among the recombinant UGTs (13 isoforms) examined, UGT2B7 and UGT2B15 were the most active of catalyzing 4-tOP glucuronidation. Although the K m values of UGT2B7 and UGT2B15 were similar (0.36 and 0.42 µM, respectively), the CL int value of UGT2B7 (6.83 mL/min/mg protein) >UGT2B15 (2.35 mL/min/mg protein). Strong correlations were observed between the glucuronidation activities of 4-tOP and diclofenac (a probe for UGT2B7) or 4-hydroxybiphenyl (a probe for UGT2B15) with 0.79–0.88 of Spearman correlation coefficient ( r s ) values. These findings demonstrate that 4-tOP glucuronidation in humans is mainly catalyzed by hepatic UGT2B7 and UGT2B15, and suggest that these UGT isoforms play important and characteristic roles in the detoxification of 4-tOP.