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Drug Metabolism and Disposition Fast Forward
First published on August 8, 2006; DOI: 10.1124/dmd.106.011379

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Sebastian Luci
Holger Kluge
Frank Hirche
Klaus Eder
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Received for publication June 8, 2006.
Revised August 3, 2006.
Accepted for publication August 4, 2006.

Clofibrate increases hepatic triiodothyronine (T3)- and thyroxine (T4)- glucuronosyltransferase activities and lowers plasma T3 and T4 concentrations in pigs

Sebastian Luci 1, Holger Kluge 1, Frank Hirche 1, Klaus Eder 1*

1 Institut fur Ernahrungswissenschaften

* Address correspondence to: E-mail: eder{at}landw.uni-halle.de

Abstract

In rats clofibrate acts as a microsomal enzyme inducer and disrupts the metabolism of thyroid hormones by increasing hepatic glucuronidation of thyroxine. Whether similar effects occur in the pig has not yet been investigated. This study was performed to investigate the effect of clofibrate treatment on metabolism of thyroid hormones in pigs. To this end, an experiment with 18 pigs was performed which were assigned to two groups. One group received a control diet, the other group was fed the same diet supplemented with 5 g clofibrate/kg, for 28 days. Pigs treated with clofibrate had higher hepatic activities of T3- and T4-uridine diphosphate-glucuronosyltransferases (UGTs) and lower concentrations of total and free T4 and total T3 in plasma than control pigs (P<0.05). Weights and histology of the thyroid gland (epithelial height, follicle lumen diameter) did not differ between the two groups, but pigs treated with clofibrate had higher mRNA concentrations of various genes in the thyroid responsive to thyroid-stimulating hormone (TSH) such as TSH receptor, sodium iodine symporter, thyroid peroxidase and cathepsin B than control pigs (P<0.05). Pigs treated with clofibrate also had lower hepatic mRNA concentrations of proteins involved in plasma thyroid hormone transport [thyroxine-binding globulin (P<0.10), transthyretin (P<0.05), albumin (P<0.05)] and thyroid hormone receptor {alpha}1 (P<0.05) than control pigs. In conclusion, this study shows that clofibrate treatment induces a strong activation of T3- and T4-UGTs in pigs, leading to increased glucuronidation and markedly reduced plasma concentrations of these hormones, accompanied by a moderate stimulation of thyroid function.


Key words: liver microsomes, peroxisome proliferator-activated receptors, phase II drug metabolism, UDP glucuronyltransferases




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