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Short-term exposure to triclosan decreases thyroxine in vivo via upregulation of hepatic catabolism in young long-evans rats
Citation:
Paul, K. B., J. M. Hedge, M. J. DEVITO, AND K. M. CROFTON. Short-term exposure to triclosan decreases thyroxine in vivo via upregulation of hepatic catabolism in young long-evans rats. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 113(2):367-379, (2010).
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research results
Description:
Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol)is a chlorinated phenolic antibacterial compound used in consumer products. Structural similarity of triclosan to thyroid hormones, in vitro activation ofthe human pregnane X receptor (PXR) and induction of hepatic Phase I enzymes, and in vivo decreases of total thyroxine (T4) suggest adverse effects on thyroid hormone homeostasis. Current research tested the hypothesis that triclosan decreases circulating T4 via upregulation ofhepatic catabolism and transport of hormones. Weanling female Long-Evans rats received triclosan (0-1000 mglkg/day) by gavage for four days. Whole blood and liver were collected 24 hours after the last dose. Hepatic microsomal assays measured ethoxyresorufin-Odeethylase (EROD), pentoxyresorufin-O-deethylase (PROD), and uridine diphosphate glucuronosyltransferase (UGT) enzyme activities. The mRNA expression of cytochrome P450s lal, 2bl/2, and 3al/23, UGTs lal, la6, and 2b5, sulfotransferases lc1 and Ibl, and hepatic transporters Oatplal, Oatpla4, Mrp2, and Mdrl b were measured by quantitative RT-PCR. Triclosan caused a dose-dependent increase in PROD activity to 900 percent of control at 1000 mglkg/day, and a small, dose-independent decrease in EROD activity. T4-g1ucuronidation increased nearly 2-fold at 1000 mg/kg/day. Cyp2bl/2 and Cyp3al/23 mRNA expression were induced 2-fold and 4-fold at 300 mg/kg/day. Ugtlal and Sultlc1 mRNA expression increased 2.2-fold and 2.6-fold at 300 mg/kg/day. No significant changes were observed for transporter mRNA expression. These data denote important key events in the mode-of-action for triclosan in rats, and suggest that triclosan-induced hypothyroxinemia is, at least partially, due to upregulation of hepatic catabolism (Phases I and II), and not due to mRNA expression changes in the tested hepatic transporters.
