title: The commonly used antimicrobial additive triclosan is a liver tumor promoter.
abstract: Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated.
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, and.
authors.forename: Mei-Fei
authors.initials: MF
authors.lastname: Yueh
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, and.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; and.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California Davis Cancer Center, University of California, Davis, CA 95616 rtukey@ucsd.edu bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, and rtukey@ucsd.edu bdhammock@ucdavis.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
mesh_terms: D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000633:toxicity; D063646:Carcinogenesis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014260:Triclosan / Q000633:toxicity*
chemical_list: D000891:Anti-Infective Agents, Local; D016207:Cytokines; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D014260:Triclosan; D000410:Alanine Transaminase
keywords: hepatocellular carcinoma; liver fibrosis; triclosan; tumor promoter