title: Glucuronidation of 4-tert-octylphenol in humans, monkeys, rats, and mice: an in vitro analysis using liver and intestine microsomes.
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 Km, Vmax, and CLintvalues 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 Km, Vmax, and CLintvalues of human intestine microsomes were 0.743 µM, 0.571 nmol/min/mg protein, and 0.770 mL/min/mg protein, respectively. The CLintvalues 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 CLintvalues 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.
authors.affiliation: Laboratory of Xenobiotic Metabolism, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-Ku, Yokohama, 245-0066, Japan. nhanioka@hamayaku.ac.jp.
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Hanioka
authors.affiliation: Laboratory of Xenobiotic Metabolism, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-Ku, Yokohama, 245-0066, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Laboratory of Environmental Toxicology, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-Ku, Yokohama, 245-0066, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohkawara
authors.affiliation: Laboratory of Environmental Toxicology, Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-Ku, Yokohama, 245-0066, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka-Kagawa
authors.affiliation: Laboratory of Hygienic Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-Ku, Nagoya, 468-8503, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Jinno
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D006801:Humans; D007422:Intestines / Q000166:cytology; D008252:Macaca fascicularis; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010636:Phenols / Q000378:metabolism / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D055815:Young Adult
chemical_list: D010636:Phenols; C105260:4-tert-octylphenol
keywords: 4-tert-Octylphenol (4-tOP); Glucuronidation; Intestine microsomes; Liver microsomes; UDP-glucuronosyltransferase (UGT)