title: Evidence for triclosan-induced activation of human and rodent xenobiotic nuclear receptors.
abstract: The bacteriostat triclosan (2,4,4'-trichloro-2'-hydroxydiphenylether) (TCS) decreases rat serum thyroxine via putative nuclear receptor (NR) interaction(s) and subsequent transcriptional up-regulation of hepatic catabolism and clearance. However, due to the evolutionary divergence of the constitutive androstane and pregnane-X receptors (CAR, PXR), TCS-mediated downstream effects may be species-dependent. To test the hypothesis that TCS activates xenobiotic NRs across species, cell-based NR reporter assays were employed to assess potential activation of rat, mouse, and human PXR, and rat, mouse, and three splice variants of human CAR. TCS activated hPXR, acted as an inverse agonist of hCAR1, and as a weak agonist of hCAR3. TCS failed to activate rPXR in full-length receptor reporter assays, and instead acted as a modest inverse agonist of rCAR. Consistent with the rat data, TCS also failed to activate mPXR and was a modest inverse agonist of mCAR. These data suggest that TCS may interact with multiple NRs, including hPXR, hCAR1, hCAR3, and rCAR in order to potentially affect hepatic catabolism. Overall these data support the conclusion that TCS may interact with NRs to regulate hepatic catabolism and downstream thyroid hormone homeostasis in both rat and human models, though perhaps by divergent mechanisms.
authors.affiliation: University of North Carolina at Chapel Hill, Curriculum in Toxicology, CB 7270, Chapel Hill, NC 27599, United States; Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, United States.
authors.forename: Katie B
authors.initials: KB
authors.lastname: Paul
authors.forename: Jerry T
authors.initials: JT
authors.lastname: Thompson
authors.forename: Steven O
authors.initials: SO
authors.lastname: Simmons
authors.forename: John P
authors.initials: JP
authors.lastname: Vanden Heuvel
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Crofton
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D054314:Drug Inverse Agonism; D017930:Genes, Reporter / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D000077297:Pregnane X Receptor; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity; D014260:Triclosan / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D014260:Triclosan
keywords: 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime; AOP; CITCO; CTZ; CYP; Constitutive androstane receptor; DEHP; DPX2; EC50; Hepatic catabolism; LBD; MIE; PB; Pregnane-X receptor; RPXR; T4; TCPOBOP; TCS; Thyroid disruption; Triclosan; adverse outcome pathway; cDNA; clotrimazole; complementary DNA; cytochrome P450; di-(2-ethylhexyl)phthalate; hCAR; hPXR; half-maximal effect concentration; human PXR; human constitutive androstane receptor; ligand binding domain; mCAR; mPXR; molecular-initiating event; mouse PXR; mouse constitutive androstane receptor; name of the hPXR model, commercial product of Puracyp, Inc; name of the rPXR model, commercial product of Puracyp, Inc; phenobarbital; rCAR; rPXR; rat PXR; rat constitutive androstane receptor; thyroxine; triclosan