Effects of microsomal enzyme inducers on outer-ring deiodinase activity toward thyroid hormones in various rat tissues.
Microsomal enzyme inducers, such as phenobarbital (PB), pregnenolone-16alpha-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB) are more effective at reducing serum thyroxine (T(4)) than serum triiodothyronine (T(3)). It is possible that rats treated with PB and PCN maintain serum T(3) by increasing serum TSH, which stimulates the thyroid gland to synthesize more T(3). However, it is unclear how serum T(3) is maintained in rats treated with 3MC or PCB, because serum TSH is not increased in these rats. We hypothesized that increased conversion of T(4) to T(3), catalyzed by outer-ring deiodinases (ORD) type-I and -II, is the reason serum T(3) is maintained in rats treated with 3MC or PCB. Furthermore, 3MC and PCB do not increase serum TSH, whereas PB and PCN do, because type-II ORD activity in the pituitary of 3MC- and PCB-treated rats is increased greater than in rats treated with PB or PCN. To test these two hypotheses, male Sprague-Dawley rats were fed either a basal diet or a diet containing PB (300, 600, 1200, or 2400 ppm), PCN (200, 400, 800, or 1600 ppm), 3MC (50, 100, 200, or 400 ppm), or PCB (25, 50, 100, or 200 ppm) for 7 days. Type-I ORD activity was measured in thyroid, kidney, and liver, whereas type-II ORD activity was measured in brown adipose tissue, pituitary, and brain. Type-I ORD activity in thyroid was not affected by PB, 3MC, or PCB treatments, and was slightly increased by PCN. Type-I ORD activity in kidney was not affected by PB, PCN, or 3MC treatments, and was reduced by PCB treatment. Type-I ORD activity in liver was reduced by PB, PCN, 3MC, and PCB treatments. Type-II ORD activity in brown adipose tissue was unaffected by any of the four treatments. Type-II ORD activity in pituitary was unaffected by PB or 3MC treatments, and was increased by PCN or PCB treatments. Type-II ORD activity in brain was unaffected by PB treatment, and was increased by PCN, 3MC, and PCB treatments. Overall, total ORD activity, calculated by summation of ORD activities in thyroid, kidney, liver, brown adipose tissue, pituitary, and brain, was reduced rather than increased by the four microsomal enzyme inducers. In conclusion, increased conversion of T(4) to T(3) is not the reason serum T(3) concentration is maintained in 3MC- or PCB-treated rats. Furthermore, the reason serum TSH is not increased in 3MC- and PCB-treated rats is the result of mechanisms other than increased type-II ORD activity in pituitary.
Hood
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Department of Pharmacology, University of Kansas Medical Center, Kansas City, Kansas, 66160-7140, USA.
Klaassen
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D000818:Animals; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects*; D007453:Iodide Peroxidase / Q000096:biosynthesis*; D007457:Iodine Radioisotopes; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013963:Thyroid Hormones / Q000378:metabolism*; D013972:Thyrotropin / Q000097:blood / Q000378:metabolism; D013974:Thyroxine / Q000097:blood / Q000378:metabolism; D014018:Tissue Distribution; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism
D007457:Iodine Radioisotopes; D011506:Proteins; D013963:Thyroid Hormones; D014284:Triiodothyronine; D020111:Chlorodiphenyl (54% Chlorine); D008748:Methylcholanthrene; D013972:Thyrotropin; D007453:Iodide Peroxidase; D013974:Thyroxine