You are here:
Triclosan Disrupts Thyroxine: Contribution of Hepatic Transport to the Mode of Action
Citation:
Paul, K. B., J. M. HEDGE, M. J. DEVITO, K. M. CROFTON, AND K. L. Brouwer. Triclosan Disrupts Thyroxine: Contribution of Hepatic Transport to the Mode of Action. Presented at Society of Toxicology 49th Annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
These data suggest that while TCS may interact with CAR and PXR to upregulate hepatic catabolism and decrease circulating T4 concentrations, TCS has minimal effects on hepatic transport of thyroid hormone into and out of the liver. This abstract does not necessarily reflect the policy ofthe US EPA or NIEHS.
Description:
Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) (TCS) decreases serum thyroxine (T4) in rats. In previous work, TCS upregulated Phase I and II hepatic metabolism after 4-day exposures in rats. A major data gap in our characterization of the mode of action (MOA) of TCS-induced hypothyroxinemia is the possible contribution of hepatic transport. To test the hypothesized MOA that triclosan decreases T4 via activation of the pregnane X and constitutive androstane· receptors (PXR and CAR), and subsequent upregulation of thyroid hormone transport, both in vivo and in vitro studies were employed. Weanling female Long-Evans rats received TCS po (01000 mg/kg/day) for 4 days. The mRNA expression of hepatic transporters Oatplal and la4, Mrp2, and Mdrl b was measured by qRT-PCR. No changes were observed in mRNA levels. Sandwich-cultured rat hepatocytes (SCRH) were treated with TCS (0-30 JlM) for 2 or 48 hours prior to assessment of hepatic uptake and biliary clearance of estradiol-Ull-glucuronide (E2-17~G) and digoxin. Only dose-independent, minor effects on functional activity were observed. 48 hour TCS treatment at 1-10 JlM increased hepatic uptake of E2-17~-G by 20%. 10 minute TCS incubation increased uptake and excretion of E2-17~-G at I JlM TCS, increased E2-17~-G . uptake 20% at 10 JlM TCS, and decreased E2-17~-G biliary excretion 10% at 30JlM TCS. No significant effects ofTCS on digoxin transport were observed. Protein content for Cyp3al, Oatplal, Oatpla4, Mdrl, Mrp2, Mrp3, and Mrp4 in SCRH was assessed by Western blotting. Triclosan increased Cyp3al 50-60% and Oatpla4 20-50% at all doses, and Mrp2 20% at 30 JlM. These data suggest that while TCS may interact with CAR and PXR to upregulate hepatic catabolism and decrease circulating T4 concentrations, TCS has minimal effects on hepatic transport of thyroid hormone into and out of the liver. This abstract does not necessarily reflect the policy ofthe US EPA or NIEHS.