title: Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha.
abstract: Triclocarban (3,4,4'-trichlorocarbanilide, TCC) is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs). To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR) and estrogen receptor alpha (ERα) activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR) because no induction occurred in hUGT1Car(-/-) mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for potential human health effects from exposure to TCC.
authors: Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California, United States of America.
authors: Mei-Fei
authors: MF
authors: Yueh
authors: Tao
authors: T
authors: Li
authors: Ronald M
authors: RM
authors: Evans
authors: Bruce
authors: B
authors: Hammock
authors: Robert H
authors: RH
authors: Tukey
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002224:Carbanilides / Q000494:pharmacology*; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D065633:Cytochrome P-450 CYP1B1; D065702:Cytochrome P-450 CYP2B6; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008658:Inactivation, Metabolic; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D000891:Anti-Infective Agents, Local; D002224:Carbanilides; D000090702:Constitutive Androstane Receptor; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015262:Xenobiotics; C009540:triclocarban; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585599:CYP2B6 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D014453:Glucuronosyltransferase