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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 activitymore » 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. - Highlights: • Metabolic modification of the endocrine-disrupting activity of BP-3 was examined. • 2,4,5-TriOH BP and 3-OH BP-3 were identified as new BP-3 metabolites. • 2,4-DiOH BP and 2,3,4-triOH BP exhibited high or similar estrogenic activities. • Estrogenic activity of BP-3 was enhanced by incubation with rat liver microsomes. • Structural requirements for the activities of BP-3 derivatives were demonstrated.« less

Authors:
 [1];  [2]; ;  [3];  [4];  [1];  [5];  [4];  [1]
  1. Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553 (Japan)
  2. (Japan)
  3. Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan)
  4. Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Saitama 362-0806 (Japan)
  5. Faculty of Pharmaceutical Science, Hiroshima International University, Koshingai 5-1-1, Kure, Hiroshima 737-0112 (Japan)
Publication Date:
OSTI Identifier:
22465675
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 282; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 3-METHYLCHOLANTHRENE; ANDROGENS; BENZOPHENONE; CHO CELLS; COMPARATIVE EVALUATIONS; DEXAMETHASONE; ESTRADIOL; FILTERS; HAIR; HUMAN POPULATIONS; IN VITRO; INCUBATION; LIVER; MICROSOMES; PHENOBARBITAL; RATS; ULTRAVIOLET RADIATION

Citation Formats

Watanabe, Yoko, E-mail: y-watanabe@nichiyaku.ac.jp, Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Saitama 362-0806, Kojima, Hiroyuki, Takeuchi, Shinji, Uramaru, Naoto, Sanoh, Seigo, Sugihara, Kazumi, Kitamura, Shigeyuki, and Ohta, Shigeru. Metabolism of UV-filter benzophenone-3 by rat and human liver microsomes and its effect on endocrine-disrupting activity. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2014.12.002.
Watanabe, Yoko, E-mail: y-watanabe@nichiyaku.ac.jp, Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Saitama 362-0806, Kojima, Hiroyuki, Takeuchi, Shinji, Uramaru, Naoto, Sanoh, Seigo, Sugihara, Kazumi, Kitamura, Shigeyuki, & Ohta, Shigeru. Metabolism of UV-filter benzophenone-3 by rat and human liver microsomes and its effect on endocrine-disrupting activity. United States. doi:10.1016/J.TAAP.2014.12.002.
Watanabe, Yoko, E-mail: y-watanabe@nichiyaku.ac.jp, Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Saitama 362-0806, Kojima, Hiroyuki, Takeuchi, Shinji, Uramaru, Naoto, Sanoh, Seigo, Sugihara, Kazumi, Kitamura, Shigeyuki, and Ohta, Shigeru. Thu . "Metabolism of UV-filter benzophenone-3 by rat and human liver microsomes and its effect on endocrine-disrupting activity". United States. doi:10.1016/J.TAAP.2014.12.002.
@article{osti_22465675,
title = {Metabolism of UV-filter benzophenone-3 by rat and human liver microsomes and its effect on endocrine-disrupting activity},
author = {Watanabe, Yoko, E-mail: y-watanabe@nichiyaku.ac.jp and Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Saitama 362-0806 and Kojima, Hiroyuki and Takeuchi, Shinji and Uramaru, Naoto and Sanoh, Seigo and Sugihara, Kazumi and Kitamura, Shigeyuki and Ohta, Shigeru},
abstractNote = {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. - Highlights: • Metabolic modification of the endocrine-disrupting activity of BP-3 was examined. • 2,4,5-TriOH BP and 3-OH BP-3 were identified as new BP-3 metabolites. • 2,4-DiOH BP and 2,3,4-triOH BP exhibited high or similar estrogenic activities. • Estrogenic activity of BP-3 was enhanced by incubation with rat liver microsomes. • Structural requirements for the activities of BP-3 derivatives were demonstrated.},
doi = {10.1016/J.TAAP.2014.12.002},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 282,
place = {United States},
year = {Thu Jan 15 00:00:00 EST 2015},
month = {Thu Jan 15 00:00:00 EST 2015}
}