Reduction of thyroid hormone levels and alteration of thyroid function by four 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-16 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 (T4), free and total triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were determined by radioimmunoassay. On Day 21, following treatment with Na131I, the thyroid glands were removed and weighed, and the amount of 131I incorporated was determined. The livers were removed and microsomes were isolated for determination of T4 UDP-GT activity. UDP-GT activity toward T4 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 T4 30-40%, whereas PCB produced a 80-90% reduction. Total T3 levels were slightly reduced by treatment with PB, PCN, and PCB, but none of the treatments decreased free T3 levels. Serum T4 levels (total and free) were found to correlate with UDP-GT activity toward T4. 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 131I uptake by PB (60%), PCN (160%), and PCB (100%). Thus, while reasonable correlations between T4 glucuronidation and reduction of serum T4 can be made, only qualified correlations between reduction of T4 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 T4 and decrease T4 levels. It appears that induction of UDP-GT plays a role in the effect of these chemicals on the thyroid gland.
Barter
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RA
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417.
Klaassen
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CD
D000284:Administration, Oral; D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood*
D013963:Thyroid Hormones; D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D011078:Polychlorinated Biphenyls; D014453:Glucuronosyltransferase; D010634:Phenobarbital