Metabolism of UV-filter benzophenone-3 by rat and human liver microsomes and its effect on endocrine-disrupting activity

• Published in: Toxicology and applied pharmacology 2015-01, Vol.282 (2), p.119-128
• Main Authors: Watanabe, Yoko, Kojima, Hiroyuki, Takeuchi, Shinji, Uramaru, Naoto, Sanoh, Seigo, Sugihara, Kazumi, Kitamura, Shigeyuki, Ohta, Shigeru
• Format: Article
• Language: English
• Subjects: 3-METHYLCHOLANTHRENE; 60 APPLIED LIFE SCIENCES; Androgen Antagonists - metabolism; Androgen Antagonists - pharmacology; ANDROGENS; Animals; Anti-androgenic activity; BENZOPHENONE; Benzophenone-3; Benzophenones - metabolism; Benzophenones - pharmacology; beta-Galactosidase - metabolism; Biotransformation; CHO CELLS; COMPARATIVE EVALUATIONS; Cricetinae; Cricetulus; Cytochrome P-450 Enzyme System - metabolism; DEXAMETHASONE; Endocrine Disruptors - metabolism; Endocrine Disruptors - pharmacology; Enzyme Induction - drug effects; ESTRADIOL; Estrogenic activity; Estrogens, Non-Steroidal - metabolism; Estrogens, Non-Steroidal - pharmacology; FILTERS; HAIR; HUMAN POPULATIONS; Humans; IN VITRO; In vitro metabolism; In Vitro Techniques; INCUBATION; LIVER; Metabolic activation; MICROSOMES; Microsomes, Liver - metabolism; PHENOBARBITAL; RATS; Rats, Sprague-Dawley; Sunscreening Agents - metabolism; Sunscreening Agents - pharmacology; Ultraviolet absorber; ULTRAVIOLET RADIATION
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2014.12.002

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. •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.