In vitro metabolism of triclosan and chemoprevention against its cytotoxicity

Yubei Li; Shouyan Xiang; Liuyin Hu; Jiajun Qian; Shuoguo Liu; Jinping Jia; Jiahua Cui

doi:10.1016/j.chemosphere.2023.139708

In vitro metabolism of triclosan and chemoprevention against its cytotoxicity

Chemosphere. 2023 Oct:339:139708. doi: 10.1016/j.chemosphere.2023.139708. Epub 2023 Aug 1.

Authors

Yubei Li¹, Shouyan Xiang², Liuyin Hu², Jiajun Qian³, Shuoguo Liu², Jinping Jia⁴, Jiahua Cui⁵

Affiliations

¹ School of China-UK Low Carbon College, Shanghai Jiaotong University, Shanghai, China.
² School of Environmental Science and Engineering, Shanghai Jiaotong University, Shanghai, China.
³ School of Chemistry and Chemical Engineering, Shanghai Jiaotong University, Shanghai, China.
⁴ School of Environmental Science and Engineering, Shanghai Jiaotong University, Shanghai, China; School of Chemistry and Chemical Engineering, Shanghai Jiaotong University, Shanghai, China.
⁵ School of Chemistry and Chemical Engineering, Shanghai Jiaotong University, Shanghai, China. Electronic address: cpucjh@sjtu.edu.cn.

PMID: 37536533
DOI: 10.1016/j.chemosphere.2023.139708

Abstract

Triclosan (TCS), a broad-spectrum antibacterial chemical, has been extensively used in personal daily care items, household commodities, and clinical medications; therefore, humans are at risk of being exposed to TCS in their daily lives. This chemical also accumulated in food chains, and potential risks were associated with its metabolism in vivo. The aim of this study was to investigate the difference in metabolic profile of TCS by hepatic P450 enzymes and extrahepatic P450s, and also identify chemical structures of its metabolites. The results showed that RLM mediated the hydroxylation and cleavage of the ether moiety of TCS, resulting in phenolic metabolites that are more polar than the parent compound, including 4-chlorocatechol, 2,4-dichlorophenol and monohydroxylated triclosan. The major metabolite of CYP1A1 and CYP1B1 mediated TCS metabolism is 4-chlorochol. We also performed molecular docking experiments to investigate possible binding modes of TCS in the active sites of human CYP1B1, CYP1A1, and CYP3A4. In addition to in vitro experiments, we further examined the cytotoxic effects of TCS on HepG2 cells expressing hepatic P450 and MCF-7/1B1 cells expressing CYP1B1. It exhibited significant cytotoxicity on HepG2, MCF-10A and MCF-7/1B1 cells, with IC₅₀ values of 70 ± 10 μM, 20 ± 10 μM and 60 ± 20 μM, respectively. The co-incubation of TCS with glutathione (GSH) as a chemopreventive agent could reduce the cytotoxicity of TCS in vitro. The chemopreventive effects of GSH might be ascribed to the promotion of TCS efflux mediated by membrane transporter MRP1 and also its antioxidant property, which partially neutralized the oxidative stress of TCS on mammalian cells. This study contributed to our understanding of the relationship between the P450 metabolism and the toxicity of TCS. It also had implications for the use of specific chemopreventive agents against the toxicity of TCS.

Keywords: CYP1A1/1B1; Chemoprevention; Metabolism; P450; Toxicity; Triclosan.

MeSH terms

Animals
Chemoprevention
Cytochrome P-450 CYP1A1 / metabolism
Cytochrome P-450 Enzyme System / metabolism
Humans
Mammals / metabolism
Molecular Docking Simulation
Phenols
Triclosan* / metabolism
Triclosan* / toxicity

Substances

Triclosan
Cytochrome P-450 CYP1A1
Cytochrome P-450 Enzyme System
Phenols