Cytochrome P450-mediated metabolism of triclosan attenuates its cytotoxicity in hepatic cells

Abstract

Triclosan is a widely used broad-spectrum anti-bacterial agent. The objectives of this study were to identify which cytochrome P450 (CYP) isoforms metabolize triclosan and to examine the effects of CYP-mediated metabolism on triclosan-induced cytotoxicity. A panel of HepG2-derived cell lines was established, each of which overexpressed a single CYP isoform, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1. The extent of triclosan metabolism by each CYP was assessed by reversed-phase high-performance liquid chromatography with online radiochemical detection. Seven isoforms were capable of metabolizing triclosan, with the order of activity being CYP1A2 > CYP2B6 > CYP2C19 > CYP2D6 ≈ CYP1B1 > CYP2C18 ≈ CYP1A1. The remaining 11 isoforms (CYP2A6, CYP2A7, CYP2A13, CYP2C8, CYP2C9, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1) had little or no activity toward triclosan. Three metabolites were detected: 2,4-dichlorophenol, 4-chlorocatechol, and 5'-hydroxytriclosan. Consistent with the in vitro screening data, triclosan was extensively metabolized in HepG2 cells overexpressing CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP2C18, and these cells were much more resistant to triclosan-induced cytotoxicity compared to vector cells, suggesting that CYP-mediated metabolism of triclosan attenuated its cytotoxicity. In addition, 2,4-dichlorophenol and 4-chlorocatechol were less toxic than triclosan to HepG2/vector cells. Conjugation of triclosan, catalyzed by human glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), also occurred in HepG2/CYP-overexpressing cells and primary human hepatocytes, with a greater extent of conjugation being associated with higher cell viability. Co-administration of triclosan with UGT or SULT inhibitors led to greater cytotoxicity in HepG2 cells and primary human hepatocytes, indicating that glucuronidation and sulfonation of triclosan are detoxification pathways. Among the 18 CYP-overexpressing cell lines, an inverse correlation was observed between cell viability and the level of triclosan in the culture medium. In conclusion, human CYP isoforms that metabolize triclosan were identified, and the metabolism of triclosan by CYPs, UGTs, and SULTs decreased its cytotoxicity in hepatic cells.

Influence of Tetrabromobisphenol A, with or without Concurrent Triclosan, upon Bisphenol A and Estradiol Concentrations in Mice

“…Whereas triclosan alone was ineffective in a uterotrophic assay of weanling rats, elevated uterine weight occurred following concurrent triclosan and ethinyl estradiol exposure ( Stoker et al 2010 ). These findings are consistent with evidence that triclosan is conjugated by SULT, UGT, and CYP ( Wu et al 2016a ) and that it can inhibit the activity of SULT and UGT toward other substances, including BPA and E2 ( James et al 2010 , 2015 ; Wang et al 2004 ).…”

Triclosan Enhances the Clearing of Pathogenic Intracellular Salmonella or Candida albicans but Disturbs the Intestinal Microbiota through mTOR-Independent Autophagy

“…Triclosan (TCS) is a broad-spectrum anti-bacterial agent whose mechanism of action is reported to be blocking fatty acid synthesis (Gaulke et al, 2016 ). TCS is widely used in a large number of personal care products, household items, medical devices, and in clinical settings (Wu et al, 2017 ). However, there is a significant increase in hepatocellular adenomas and carcinomas in mice treated with TCS (Fang et al, 2010 ).…”

Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals

“…However, the transcriptomic profile of two donors (S1391T and S1506T, males) being exposed to TRI clearly suggested disrupted hepatocyte homeostasis. Even though we cannot exclude the existence of gender-related differences in the response to TRI, the relative decreased sensitivity of donor S1353T (female) towards TRI alone might be explained by the observed upregulation of CYP2B6, as previously denoted [51]. Likewise, the increased susceptibility to the co-incubation with BAs could be derived from the observed upregulation of CYP7A1 possibly leading to increased basal BA levels.…”