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Glucuronidation of 4-tert-octylphenol in humans, monkeys, rats, and mice: an in vitro analysis using liver and intestine microsomes

  • 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 mammals. In the present study, the glucuronidation of 4-tOP in humans, monkeys, rats, and mice was examined in an in vitro system using microsomal fractions. The kinetics of 4-tOP glucuronidation by liver microsomes followed the Michaelis–Menten model for humans and monkeys, and the biphasic model for rats and mice. The K m, V max, and CL int values of human liver microsomes were 0.343 µM, 11.6 nmol/min/mg protein, and 33.8 mL/min/mg protein, respectively. The kinetics of intestine microsomes followed the Michaelis–Menten model for humans, monkeys, and rats, and the biphasic model for mice. The K m, V max, and CL int values of human intestine microsomes were 0.743 µM, 0.571 nmol/min/mg protein, and 0.770 mL/min/mg protein, respectively. The CL int values estimated by Eadie–Hofstee plots were in the order of mice (high-affinity phase) (3.0) > humans (1.0) ≥ monkeys (0.9) > rats (high-affinity phase) (0.4) for liver microsomes, and monkeys (10) > mice (high-affinity phase) (5.6) > rats (1.4) > humans (1.0) for intestine microsomes. The percentages of the CL int values of intestine microsomes to liver microsomes were in the order of monkeys (27 %) > rats (high-affinity phase in liver microsomes) (7.9 %) > mice (high-affinity phase in liver and intestine microsomes) (4.2 %) > humans (2.3 %). These results suggest that the metabolic abilities of UGT enzymes expressed in the liver and intestine toward 4-tOP markedly differ among species and imply that species differences are strongly associated with the toxicities of alkylphenols.

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Abbreviations

4-tOP:

4-tert-Octylphenol

UGT:

UDP-glucuronosyltransferase

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Acknowledgments

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

    Nobumitsu Hanioka & Takashi Isobe

  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

Authors
  1. Nobumitsu Hanioka
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  2. Takashi Isobe
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  3. Susumu Ohkawara
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  4. Toshiko Tanaka-Kagawa
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  5. Hideto Jinno
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Correspondence to Nobumitsu Hanioka.

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Hanioka, N., Isobe, T., Ohkawara, S. et al. Glucuronidation of 4-tert-octylphenol in humans, monkeys, rats, and mice: an in vitro analysis using liver and intestine microsomes. Arch Toxicol 91, 1227–1232 (2017). https://doi.org/10.1007/s00204-016-1800-1

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  • DOI: https://doi.org/10.1007/s00204-016-1800-1

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