Article ; Online: Evidence for triclosan-induced activation of human and rodent xenobiotic nuclear receptors.
Toxicology in vitro : an international journal published in association with BIBRA
2013 Volume 27, Issue 7, Page(s) 2049–2060
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 ... ...
| 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. |
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| MeSH term(s) | Animals ; Anti-Bacterial Agents/pharmacology ; Anti-Infective Agents, Local/pharmacology ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Drug Inverse Agonism ; Genes, Reporter/drug effects ; HEK293 Cells ; Hep G2 Cells ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; Kinetics ; Mice ; Models, Biological ; Protein Isoforms/agonists ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Rats ; Receptors, Cytoplasmic and Nuclear/agonists ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Steroid/agonists ; Receptors, Steroid/genetics ; Receptors, Steroid/metabolism ; Recombinant Fusion Proteins/biosynthesis ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/metabolism ; Species Specificity ; Triclosan/pharmacology |
| Chemical Substances | Anti-Bacterial Agents ; Anti-Infective Agents, Local ; Protein Isoforms ; Receptors, Cytoplasmic and Nuclear ; Receptors, Steroid ; Recombinant Fusion Proteins ; constitutive androstane receptor ; pregnane X receptor ; Triclosan (4NM5039Y5X) |
| Language | English |
| Publishing date | 2013-10 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 639064-x |
| ISSN | 1879-3177 ; 0887-2333 |
| ISSN (online) | 1879-3177 |
| ISSN | 0887-2333 |
| DOI | 10.1016/j.tiv.2013.07.008 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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