| Microsomal enzyme inducers that increase thyroxine (T$sb4)$ glucuronidation are suspected to promote thyroid tumors in rats. It is proposed that microsomal enzyme inducers promote thyroid tumors because they increase the metabolism and elimination of T$sb4,$ which results in a reduction in serum T$sb4$ concentration. In response to reduced serum T$sb4,$ serum thyroid stimulating hormone (TSH) concentration increases. TSH stimulates the thyroid gland function, growth, and ultimately neoplasia.;Only one microsomal enzyme inducer, phenobarbital (PB), has been shown to promote thyroid tumors, other microsomal enzyme inducers have not been tested for their thyroid tumor promoting potential. However, several microsomal enzyme inducers have been shown to increase the glucuronidation of T$sb4$ and reduce serum T$sb4$ concentration, which include PB, pregnenolone-16$alpha$-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB). Of these microsomal enzyme inducers, only PB and PCN have been shown to increase serum TSH, whereas 3MC and PCB do not increase serum TSH. This suggests that the glucuronidation of T$sb4$ may not be important in increasing serum TSH in microsomal enzyme inducer treated rats.;I hypothesized that only those microsomal enzyme inducers that increase serum TSH concentration, e.g., PB and PCN, increase thyroid gland growth, whereas those microsomal enzyme inducers that do not increase serum TSH, e.g., 3MC and PCB, do not affect thyroid gland growth. The reason 3MC and PCB do not increase serum TSH is because these microsomal enzyme inducers increase the synthesis of T$sb3,$ which maintains the negative feedback effect on TSH synthesis and secretion.;The effects of PB and PCN on thyroid gland growth was determined in a 90-day study. Phenobarbital and PCN increased thyroid gland weight in rats treated for 14 days and remained increased in rats treated for longer periods of time. Thyroid follicular cell proliferation peaked in rats treated for 7 days.;Conversion of T$sb4$ to T$sb3,$ catalyzed by outer-ring deiodinases (ORD), is the major pathway for the synthesis of T$sb3.$ In contrast to our hypothesis, ORD activity was dose-dependently reduced in rats treated with microsomal enzyme inducers. Therefore, it was hypothesized that the reason PB and PCN increase serum TSH is because these microsomal enzyme inducers increase the metabolism of T$sb3,$ the biologically active thyroid hormone, whereas 3MC and PCB do not increase serum TSH because these microsomal enzyme inducers do not alter the metabolism of T$sb3.$ Sulfotransferase activity was not affected by the four microsomal enzyme inducers. In contrast, T$sb3$UDP-glucuronosyl-transferase activity was dose-dependently increased in PB- and PCN-treated rats, but not rats treated with 3MC or PCB.;In conclusion, findings from these studies support the hypothesis that only those microsomal enzyme inducers that increase serum TSH will increase thyroid gland growth, because thyroid gland growth is TSH-dependent. (Abstract shortened by UMI.). |
