Benzotriazole UV 328 and UV-P showed distinct antiandrogenic activity upon human CYP3A4-mediated biotransformation

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...

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Published in:Environmental pollution (1987) 2017-01, Vol.220 (Pt A), p.616-624
Main Authors: Zhuang, Shulin, Lv, Xuan, Pan, Liumeng, Lu, Liping, Ge, Zhiwei, Wang, Jiaying, Wang, Jingpeng, Liu, Jinsong, Liu, Weiping, Zhang, Chunlong
Format: Article
Language:English
Subjects:
Androgen Antagonists - analysis
Androgen Antagonists - chemistry
Androgen Antagonists - metabolism
Androgen Antagonists - toxicity
Androgen receptor
Benzotriazole UV stabilizers
Biological Assay
Biotransformation
Chromatography, High Pressure Liquid
Cytochrome P-450 CYP3A - metabolism
Environmental Monitoring
Environmental Pollution - adverse effects
Environmental Pollution - analysis
Humans
Mass spectrometry
Metabolism
Molecular modeling
Public Health
Receptors, Androgen - metabolism
Tandem Mass Spectrometry
Triazoles - chemistry
Triazoles - metabolism
Triazoles - radiation effects
Triazoles - toxicity
Ultraviolet Rays
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Summary: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. [Display omitted] •Two of the 8 BUVSs (UV-328 and UV-P) showed altered toxicity upon metabolism.•UV-328 showed more potent antiandrogenic activity after CYP3A4-mediated metabolism.•UV-328 can be metabolized into mono- and di-hydroxylated (OH) metabolites.•Sites of metabolism of UV-328 occur mainly at the alicyclic hydrocarbon atom.•Hydroxylation of BUVSs may present risk concern to human health. Our study filled the knowledge gap that UV-328 and UV-P showed significantly altered toxicity upon CYP3A4-mediated metabolism, which should be considered during the risk assessment.
ISSN:0269-7491
1873-6424
DOI:10.1016/j.envpol.2016.10.011