Induction of T(4) UDP-GT activity, serum thyroid stimulating hormone, and thyroid follicular cell proliferation in mice treated with microsomal enzyme inducers.
The microsomal enzyme inducers phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB) are known to induce thyroxine (T(4)) glucuronidation and reduce serum T(4) concentrations in rats. Also, microsomal enzyme inducers that increase serum TSH (i.e., PB and PCN) also increase thyroid follicular cell proliferation in rats. Little is known about the effects of these microsomal enzyme inducers on T(4) glucuronidation, serum thyroid hormone concentrations, serum TSH, and thyroid gland growth in mice. Therefore, we tested the hypothesis that microsomal enzyme inducers induce T(4) UDP-GT activity, resulting in reduced serum T(4) concentrations, as well as increased serum TSH and thyroid follicular cell proliferation in mice. B6C3F male mice were fed a control diet or a diet containing PB (600, 1200, 1800, or 2400 ppm), PCN (250, 500, 1000, or 2000 ppm), 3MC (62.5, 125, 250, or 500 ppm), or PCB (10, 30, 100, or 300 ppm) for 21 days. All four inducers increased liver weight and hepatic microsomal UDP-GT activity toward chloramphenicol, alpha-naphthol, and T(4). PB and PCB decreased serum total T(4), but PCN and 3MC did not. Serum thyroid stimulating hormone was markedly increased by PCN and 3MC treatments, and slightly increased by PB and PCB treatments. All four microsomal enzyme inducers dramatically increased thyroid follicular cell proliferation in mice. The findings suggest that PB, PCN, 3MC, and PCB disrupt thyroid hormone homeostasis in mice.
Hood
Alan
A
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7140, USA.
Allen
Marcia L
ML
Liu
YaPing
Y
Liu
Jie
J
Klaassen
Curtis D
CD
D000284:Administration, Oral; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D013961:Thyroid Gland / Q000187:drug effects / Q000201:enzymology*; D013972:Thyrotropin / Q000097:blood*
D020111:Chlorodiphenyl (54% Chlorine); D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D013972:Thyrotropin; C117189:thyroxine-UDP-glucuronosyltransferase; D014453:Glucuronosyltransferase; D010634:Phenobarbital