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Effects of a Model Inducer, Phenobarbital, on Thyroid Hormone Glucuronidation in Rat Hepatocytes
Citation:
RICHARDSON, V. M. AND M. J. DEVITO. Effects of a Model Inducer, Phenobarbital, on Thyroid Hormone Glucuronidation in Rat Hepatocytes. Presented at 2009 Annual Society of Toxicology meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
In vivo, hepatic enzyme inducers such as phenobarbital (PB) decrease circulating thyroid hormone (TH) concentrations. This decrease in circulating TH occurs in part through extrathyroidal mechanisms. Specifically, through the induction of hepatic xenobiotic metabolizing enzymes such as uridinediphosphate-glucoronosyltransferases (UGTs), thyroid hormones are catabolized and cleared through biliary elimination.
Description:
In vivo, hepatic enzyme inducers such as phenobarbital (PB) decrease circulating thyroid hormone (TH) concentrations. This decrease in circulating TH occurs in part through extrathyroidal mechanisms. Specifically, through the induction of hepatic xenobiotic metabolizing enzymes such as uridinediphosphate-glucoronosyltransferases (UGTs), thyroid hormones are catabolized and cleared through biliary elimination. This study further examines the catabolism and clearance of THs through the analyzing the formation of T4-glucuronide (T4G) using rat cryopreserved hepatocytes. Hepatocytes were plated in a monolayer and treated for 72 hours in serum-free media with or without 1mM PB. After removal of media, 0.05, 5.0, 25.0, or 50.0uM T4I125 was added to cells and incubated for up to 24 hours at 37C. After 24 hours, 3.3, 4.3, 4.5, and 5.7 % T4I125 is found within the hepatocytes at 0.05, 5.0, 25.0, and 50.0uM T4I125, respectively. A reduced amount of T4I125 was found within hepatocytes pretreated with 1mM PB. 2.1, 2.8, 3.2, and 4.3% was found within hepatocytes at 0.05, 5.0, 25.0, and 50.0uM T4I125, respectively following 1mM PB exposure. The Km for T4G formation following PB pretreatment was 112.4uM whereas the Km without PB was 44.7uM. These data suggest that pretreatment with PB increased the elimination of T4I125 through an increase in T4 catabolism and clearance. This study also demonstrates that rat hepatocytes are a valuable tool for evaluating the effects of xenobiotics on extrathyroidal mechanisms of T4 elimination. (This is an abstract of a proposed presentation and does not necessarily reflect USEPA policy.)