Dose-response examination of UDP-glucuronosyltransferase inducers and their ability to increase both TGF-beta expression and thyroid follicular cell apoptosis.

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-16alpha-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-beta1, 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-beta1 protein 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-beta1. PB and PCN, UDP-GT inducing compounds which increase serum TSH, increased the percentage of TGF-beta1-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-beta production. These data suggest that the increase of TGF-beta by TSH may serve to regulate the growth of hyperplastic thyroid.