REDUCTION OF THYROID-HORMONE LEVELS AND ALTERATION OF THYROID-FUNCTION BY 4 REPRESENTATIVE UDP-GLUCURONOSYLTRANSFERASE INDUCERS IN RATS

Male Sprague-Dawley rats (250-275 g) were fed diets containing four representative UDP-glucuronosyltransferase (UDP-GT) inducers, phenobarbital (PB), 3-methylcholanthrene (3MC), and pregnenolone-1 6 alpha-carbonitrile (PCN), as well as a polychlorinated biphenyl (PCB) mixture for 21 days to determine their effect on thyroid hormone levels and thyroid gland function. On Days 3, 7, 14, and 20, blood was collected and serum levels of free and total thyroxine (T-4), free and total triiodothyronine (T-3), and thyroid-stimulating hormone (TSH) were determined by radioimmunoassay. On Day 21, following treatment with (NaI)-I-131, the thyroid glands were removed and weighed, and the amount of I-131 incorporated was determined. The livers were removed and microsomes were isolated for determination of T-4 UDP-GT activity. UDP-GT activity toward T-4 was increased by PB, 3MC, PCN, and PCB approximately 190, 290, 260, and 550%, respectively, per kilogram of body weight. PB, 3MC, and PCN reduced serum total and free T-4 30-40%, whereas PCB produced a 80-90% reduction. Total T-4 levels were slightly reduced by treatment with PB, PCN, and PCB, but none of the treatments decreased free T-3 levels. Serum T-4 levels (total and free) were found to correlate with UDP-GT activity toward T-4. The reductions in thyroid hormone levels led to an increase in TSH levels by PB, 3MC, PCN, and PCB (approximately 50, 50, 210, and 40%, respectively) on Day 20. The elevation of TSH led to an increase in thyroid gland weight by PCN (60%) and PCB (30%) and an increase in thyroidal I-131 uptake by PB (60%), PCN (160%), and PCB (100%). Thus, while reasonable correlations between T-4 glucuronidation and reduction of serum T-4 can be made, only qualified correlations between reduction of T-4 and increase in TSH and increase in TSH and stimulation of the thyroid can be made. In conclusion, three classes of microsomal enzyme inducers, represented by PB, 3MC, PCN, as well as PCB, increase UDP-GT activity toward T-4 and decrease T-4 levels. It appears that induction of UDP-GT plays a role in the effect of these chemicals on the thyroid gland. (C) 1994 Academic Press, Inc.