Toxicological Sciences 55, 78-84 (2000)
Copyright © 2000 by the Society of Toxicology
Endocrine Toxicology |
Differential Effects of Microsomal Enzyme Inducers on in Vitro Thyroxine (T4) and Triiodothyronine (T3) Glucuronidation
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7140
Microsomal enzyme inducers that increase UDP-glucuronosyltransferase (UDP-GT) activity are suspected to affect the thyroid gland by increasing the glucuronidation of T4, which reduces serum thyroxine (T4). In response to reduced serum T4, serum thyroid-stimulating hormone (TSH) increases. However, not all microsomal enzyme inducers that reduce serum T4 produce an increase in serum TSH. We have shown that serum TSH is increased the most in rats treated with the microsomal enzyme inducers phenobarbital (PB) or pregnenolone-16
-carbonitrile (PCN), whereas TSH is affected less in rats treated with 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB). It is unclear why serum TSH is differentially affected by various microsomal enzyme inducers. We propose that the glucuronidation of T3 might be the reason serum TSH is increased by some microsomal enzyme inducers but not by others. Male Sprague-Dawley rats were fed either a basal diet or a diet containing PB (at 300, 600, 1200, or 2400 ppm), PCN (at 200, 400, 800, or 1600 ppm), 3MC (at 50, 100, 200, or 400 ppm), or PCB (at 25, 50, 100, or 200 ppm) for 7 days; and T4 and T3 UDP-GT activities were then determined. T4 UDP-GT activity was increased in rats treated with PB (120%), PCN (250 to 400%), 3MC (400 to 600%), or PCB (300 to 430%). In contrast, T3 UDP-GT activity was increased in rats treated with PB (90%) or PCN (120 to 200%), whereas 3MC and PCB treatments did not have an appreciable effect. In conclusion, differential effects on T3 glucuronosyltransferase activity were found in rats treated with microsomal enzyme inducers.
Key Words: UDP-glucuronosyltransferase (UDP-GT) activity; thyroid stimulating hormone (TSH); phenobarbital (PB); pregnenolone-16-carbonitrile; Arochlor 1254 (PCB); 3-methylcholanthrine; glucuronidation.
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