title: Metabolism of UV-filter benzophenone-3 by rat and human liver microsomes and its effect on endocrine-disrupting activity.
abstract: Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as sunscreen for protection of human skin and hair from damage by ultraviolet (UV) radiation. In this study, we examined the metabolism of BP-3 by rat and human liver microsomes, and the estrogenic and anti-androgenic activities of the metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified as metabolites, together with previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), a 4-desmethylated metabolite (2,4-diOH BP) and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP). In studies with recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly formed by CYP1A1. BP-3 was also metabolized by human liver microsomes and CYP isoforms. In estrogen reporter (ER) assays using estrogen-responsive CHO cells, 2,4-diOH BP exhibited stronger estrogenic activity, 2,3,4-triOH BP exhibited similar activity, and 5-OH BP-3, 2,4,5-triOH BP and 3-OH BP-3 showed lower activity as compared to BP-3. Structural requirements for activity were investigated in a series of 14 BP-3 derivatives. When BP-3 was incubated with liver microsomes from untreated rats or phenobarbital-, 3-methylcholanthrene-, or acetone-treated rats in the presence of NADPH, estrogenic activity was increased. However, liver microsomes from dexamethasone-treated rats showed decreased estrogenic activity due to formation of inactive 5-OH BP-3 and reduced formation of active 2,4-diOH BP. Anti-androgenic activity of BP-3 was decreased after incubation with liver microsomes.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan; Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Saitama 362-0806, Japan. Electronic address: y-watanabe@nichiyaku.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Saitama 362-0806, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Uramaru
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Sanoh
authors.affiliation: Faculty of Pharmaceutical Science, Hiroshima International University, Koshingai 5-1-1, Kure, Hiroshima 737-0112, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Saitama 362-0806, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
mesh_terms: D000726:Androgen Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000378:metabolism* / Q000494:pharmacology*; D001711:Biotransformation; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D052244:Endocrine Disruptors / Q000378:metabolism* / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013473:Sunscreening Agents / Q000378:metabolism* / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D001577:Benzophenones; D052244:Endocrine Disruptors; D004968:Estrogens, Non-Steroidal; D013473:Sunscreening Agents; D003577:Cytochrome P-450 Enzyme System; C005290:oxybenzone; D001616:beta-Galactosidase
keywords: Anti-androgenic activity; Benzophenone-3; Estrogenic activity; In vitro metabolism; Metabolic activation; Ultraviolet absorber