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.
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Date of publication: 27 July 2013 (Online); Toxicology in Vitro, October 2013
Author information: Katie B. Paul (1,2); Jerry T. Thompson (3); Steven O. Simmons (2); John P. Vanden Heuvel (3,4); & Kevin M. Crofton (5)
(1) University of North Carolina at Chapel Hill, Curriculum in Toxicology, CB 7270, Chapel Hill, NC 27599, United States
(2) INtegrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, United States
(3) Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA 16802, United States
(4) INDIGO Biosciences, State College, PA 16801, United States
(5) National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, RTP, NC 2711, United States