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

  • Toxicokinetics and Metabolism
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Abstract

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 CLint 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 CLint 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.

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Abbreviations

r s :

Spearman correlation coefficient

4-tOP:

4-tert-Octylphenol

UGT:

UDP-glucuronosyltransferase

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research (26281028) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Laboratory of Xenobiotic Metabolism, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, 245-0066, Japan

    Takashi Isobe & Nobumitsu Hanioka

  2. Laboratory of Environmental Toxicology, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, 245-0066, Japan

    Susumu Ohkawara & Toshiko Tanaka-Kagawa

  3. Laboratory of Hygienic Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan

    Hideto Jinno

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  1. Takashi Isobe
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  2. Susumu Ohkawara
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Correspondence to Nobumitsu Hanioka.

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Isobe, T., Ohkawara, S., Tanaka-Kagawa, T. et al. Hepatic glucuronidation of 4-tert-octylphenol in humans: inter-individual variability and responsible UDP-glucuronosyltransferase isoforms. Arch Toxicol 91, 3543–3550 (2017). https://doi.org/10.1007/s00204-017-1982-1

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