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

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 o...

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Bibliographic Details
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
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Summary: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.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2014.12.002