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Dose–Response Examination of UDP-Glucuronosyltransferase Inducers and Their Ability to Increase both TGF-β Expression and Thyroid Follicular Cell Apoptosis

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Abstract

Exposure to certain microsomal enzyme inducers that increase UDP-glucuronosyltransferase (UDP-GT) activity decreases thyroid hormone levels, which may lead to a subsequent increase in thyroid-stimulating hormone (TSH). This elevation of serum TSH has many effects on the thyroid, including increasing thyroid follicular cell proliferation, leading to hyperplasia. While induction of UDP-GT activity decreases thyroid hormone levels by enhancing biotransformation and subsequent biliary secretion, only certain UDP-GT inducers exhibit the ability to increase serum TSH levels. For example, phenobarbital (PB) and pregnenolone-16α-carbonitrile (PCN) increase serum levels of TSH, while 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB) do not. Increased serum TSH concentration also enhances thyroid gland expression of TGF-β1, an anti-proliferative, pro-apoptotic protein. In a previous study in our laboratory, rats were treated for various times (up to 90 days) with PB and PCN, which increased TGF-β1protein and apoptosis. The present study was designed to examine the dose–response effect of TSH-increasing (PB and PCN) and nonincreasing (3MC and PCB) UDP-GT inducers on apoptosis and TGF-β1. PB and PCN, UDP-GT inducing compounds which increase serum TSH, increased the percentage of TGF-β1-positive follicular cells and increased apoptosis. In contrast, UDP-GT inducers that did not increase TSH (3MC and PCB) did not alter cell death or TGF-β production. These data suggest that the increase of TGF-β by TSH may serve to regulate the growth of hyperplastic thyroid.

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    This work was supported in part by USPHS Grant ES-03192.

    2

    This author was supported in part by USPHS Training Grant ES-07079, NRSA ES-05812, and the Kansas Health Foundation.

    3

    To whom correspondence and reprint requests should be addressed at Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160-7417. Fax: (913) 588-7501; E-mail:[email protected].

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