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BDE 47 AND PCB 153 INCREASE THYROXINE CATABOLISM IN PRIMARY RAT AND HUMAN HEPATOCYTES: THE UTILITY OF HEPATOCYTES AS SCREENING TOOLS FOR POTENTIAL THYROID HORMONE DISRUPTORS
Citation:
RICHARDSON, V., Y. Sey, AND M. DeVito. BDE 47 AND PCB 153 INCREASE THYROXINE CATABOLISM IN PRIMARY RAT AND HUMAN HEPATOCYTES: THE UTILITY OF HEPATOCYTES AS SCREENING TOOLS FOR POTENTIAL THYROID HORMONE DISRUPTORS. Presented at International Symposium on Halogenated Persistent Organic Pollutants, Brussels, BELGIUM, August 21 - 25, 2011.
Impact/Purpose:
Our data supports the idea that hepatic enzyme inducers increase the hepatic metabolism of thyroid hormones by xenobiotics which in part may decrease circulating thyroid hormone concentrations in rats and humans; however, the mechanisms are still unclear. This is an abstract of a proposed presentation and does not necessarily reflect EPA or NIEHS/NTP policy.
Description:
Studies demonstrate that exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) and 2,2',4,4',5,5'· hexachlorobiphenyl (PCB 153) decrease serum thyroxine (T4)levels in laboratory animals 1,2,3. The T4 decrease in rodents is thought to occur through the induction of UDP-glucuronoysyltransferases (UGT) resulting in enhanced catabolism of T4. Although, studies exposing UGTIA-deficient Gunn rats to phenobarbital (PB) or polychlorinated biphenyl (PCB) demonstrated that serum total T4 decreases were not necessarily glucuronidation dependent" 4,5. This suggests that other mechanisms must be involved in the thyroid hormone decreases. Similar to UGTs, sulfotransferases (SULTs) are regulated by nuclear receptors',6,7; however, unlike UGTs, most prototypical nuclear receptor activators do not markedly induce SULTs in rodents"8. The lack of significant inductions by nuclear receptor activators suggests that rodent sulfation is not as essential as glucuronidation in thyroid hormone catabolism. Although the induction of human T4 sulfation by xenobiotics has yet to be examined, studies have compared thyroid hormone sulfation in human and rat. While human and rat SULTs catalyze thyroid hormones, there appears to be species differences in SULT activity. For example, even though there is an 80% amino acid sequence homology between human and rat SULTIAI,9,10, human SULTIAI catalyzes thyroid hormones while the rat isoform does not. Human SULTIAI was also identified as a low Km sulfotransferase with similar Kms and thyroid hormone substrate specificities as human hepatic and renal sulfotransferases11.12.. This correlation between human SULTIAI and sulfotransferase activites toward thyroid hormones suggests that human SULTIAI is a prominent sulfotransferase in liver and kidney. This study focuses on the enhanced formation of T4-glucuronide (T4G) in rat and human hepatocytes following exposure to PCB 153 and BDE 47. This study also highlights the utility of primary hepatocytes in evaluating potential species differences in the effects of thyroid hormone disruptors,