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Title: Induction of rat hepatic thyroid hormone metabolism by microsomal enzyme inducers : role in thyroid homeostasis
Author: Gregory, Lisa G.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2000
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Many drugs and xenobiotics cause alterations in thyroid hormone homeostasis by increasing iodothyronine metabolism and hence clearance. Consequently thyroid stimulating hormone (TSH) release is increased, which results in thyroid toxicity in rodent toxicity tests. The aim of this study was to investigate a range of microsomal enzyme inducers for their ability to increase hepatic thyroid hormone metabolism. Induction of UGT activity has been well characterised. Therefore this project focused on induction of deiodination both in vivo and in vitro. In addition to increasing UDP-glucuronosyltransferase (UGT) activity towards T4, treatment of animals with 3-methylcholanthrene (3MC), dexamethasone (Dex) and triiodothyronine (T3) resulted in increased type I deiodinase (DI) activity of up to five-fold, measured in hepatic microsomal fractions in the presence of the reducing cosubstrate dithiothreitol (DTT). To determine whether the effect of inducers on DI activity is a direct effect at the level of the hepatocyte, cells were cultured and treated in vitro. Treatment of hepatocytes with Dex, 3MC, benzanthracene (BA) and T3 increased type I DI activity which was paralleled by increased mRNA expression. Clofibrate had no significant effect when added on its own but further increased the activity and expression of the type I DI when added in combination with Dex and BA. There was an excellent correlation between activity and expression suggesting that the increased activity was a reflection of increased transcription and translation of the type I DI. Surprisingly, in the absence of DTT, DI activity was increased up to 28-fold in microsomal fractions prepared from rats treated with 3MC, clofibrate (Clof) or dexamethasone (Dex). Unlike the type I DI the activity of the novel enzyme was not inhibited by propylthiouracil, which was therefore used as a tool to differentiate between DI activity mediated by the type I and novel enzymes. In contrast to the type I DI, the activity of the novel DI is dose dependently inhibited by DTT. The type I and novel DIs also have different substrate specificities. rT3 is the preferred substrate of the type I, whereas the novel DI has a preference for T4 and T3 as substrates, and rT3 is poorly metabolised. The activities of the two DI enzymes are differentially regulated by intracellular redox status. Depletion of intracellular reduced glutathione levels with a concomitant increase in glutathione disulphide decreased type I DI activity and permitted detection of the novel DI in cultures treated with Dex. Overall induction of T4 metabolism was correlated with a decrease in the levels of serum free T4 and T3, which resulted in increased secretion of TSH. Thus the DIs, like the UGTs, are inducible by microsomal enzyme inducers and increased activity of these enzymes results in increased clearance of the thyroid hormones. The type I DI mediates thyroid hormone deiodination under normal physiological conditions, however, in conditions where intracellular redox status is perturbed, such as diabetes, atherosclerosis, chronic alcoholism and paracetamol overdose the novel DI is proposed to mediate deiodination. Induction of deiodination may be particularly important in man, where it accounts for 80% of total thyroid hormone metabolism, compared with only 50% in the rat.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available