title: Benzotriazole UV 328 and UV-P showed distinct antiandrogenic activity upon human CYP3A4-mediated biotransformation.
abstract: Benzotriazole ultraviolet stabilizers (BUVSs) are prominent chemicals widely used in industrial and consumer products to protect against ultraviolet radiation. They are becoming contaminants of emerging concern since their residues are frequently detected in multiple environmental matrices and their toxicological implications are increasingly reported. We herein investigated the antiandrogenic activities of eight BUVSs prior to and after human CYP3A4-mediated metabolic activation/deactivation by the two-hybrid recombinant human androgen receptor yeast bioassay and the in vitro metabolism assay. More potent antiandrogenic activity was observed for the metabolized UV-328 in comparison with UV-328 at 0.25 μM ((40.73 ± 4.90)% vs. (17.12 ± 3.00)%), showing a significant metabolic activation. In contrast, the metabolized UV-P at 0.25 μM resulted in a decreased antiandrogenic activity rate from (16.08 ± 0.95)% to (6.91 ± 2.64)%, indicating a metabolic deactivation. Three mono-hydroxylated (OH) and three di-OH metabolites of UV-328 were identified by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS/MS), which were not reported previously. We further surmised that the hydroxylation of UV-328 occurs mainly at the alicyclic hydrocarbon atoms based on the in silico prediction of the lowest activation energies of hydrogen abstraction from C-H bond. Our results for the first time relate antiandrogenic activity to human CYP3A4 enzyme-mediated hydroxylated metabolites of BUVSs. The biotransformation through hydroxylation should be fully considered during the health risk assessment of structurally similar analogs of BUVSs and other emerging contaminants.
authors.affiliation: Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Health Risk Factors for Seafood of Zhejiang Province, Zhoushan 316022, China. Electronic address: shulin@zju.edu.cn.
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China; Guangzhou Key Laboratory of Environmental Exposure and Health, School of Environment, Jinan University, Guangzhou 510632, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Lv
authors.affiliation: Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Liumeng
authors.initials: L
authors.lastname: Pan
authors.affiliation: Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jingpeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Zhejiang Province Environmental Monitoring Center, Hangzhou 310005, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Biological and Environmental Sciences, University of Houston-Clear Lake, 2700 Bay Area Blvd., Houston, TX 77058, USA. Electronic address: zhang@uhcl.edu.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000726:Androgen Antagonists / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001681:Biological Assay; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004784:Environmental Monitoring; D004787:Environmental Pollution / Q000009:adverse effects / Q000032:analysis*; D006801:Humans; D011634:Public Health; D011944:Receptors, Androgen / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism* / Q000528:radiation effects* / Q000633:toxicity; D014466:Ultraviolet Rays
chemical_list: D000726:Androgen Antagonists; D011944:Receptors, Androgen; D014230:Triazoles; C012771:benzotriazole; D051544:Cytochrome P-450 CYP3A
keywords: Androgen receptor; Benzotriazole UV stabilizers; Mass spectrometry; Metabolism; Molecular modeling