Metabolic fate and mechanism of toxicity caused by AhR activation derived from benzotriazole UV stabilizers

Research Project

Project/Area Number	16K21710
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Hygiene and public health Risk sciences of radiation and chemicals
Research Institution	Osaka Institute of Public Health
Principal Investigator	Nagayoshi Haruna 地方独立行政法人大阪健康安全基盤研究所, 衛生化学部, 主任研究員 (70516757)
Project Period (FY)	2016-04-01 – 2018-03-31
Project Status	Completed (Fiscal Year 2017)
Budget Amount *help	¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000) Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords	ベンゾトリアゾール系紫外線吸収剤 / AhR / シトクロムP450 / DNA損傷 / 酸化的代謝 / 紫外線吸収剤 / チトクロムP450 / 代謝 / AhR活性 / ダイオキシン
Outline of Final Research Achievements	In this study, risk assessment of 4 types of benzotriazole ultraviolet stabilizers (BUVSs) which show AhR ligand activities was attempted. First, oxidation of BUVSs by 8 types of major cytochrome P450s and changes in AhR ligand activity caused by oxidation were evaluated. As a result, BUVSs were oxidized by both AhR-dependent and independent cytochrome P450s, then, lose their original AhR ligand activity. It means that BUVSs would be categorized "no risk AhR ligand". Metabolite search was also conducted using LC-MS/MS, then UV-P and UV-9 confirmed the presence of oxidative metabolites. In addition, when the DNA damage property of BUVSs was evaluated using umu test, all BUVSs except for UV-326 were negative. From above, BUVSs other than UV-326 were considered as harmless low-risk AhR ligands. In the case of UV-326, it showed nearly positive response by umu test, therefore, comprehensive genotoxicity assessment were required.