Disruption of thyroid hormone homeostasis in Ugt1a-deficient Gunn rats by microsomal enzyme inducers is not due to enhanced thyroxine glucuronidation.
Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) are thought to increase glucuronidation of thyroxine (T(4)), thus reducing serum T(4), and subsequently increasing thyroid stimulating hormone (TSH). Ugt1a1 and Ugt1a6 mediate T(4) glucuronidation. Therefore, this experiment determined the involvement of Ugt1a enzymes in increased T(4) glucuronidation, decreased serum T(4), and increased TSH after MEI treatment. Male Wistar and Ugt1a-deficient Wistar (Gunn) rats were fed a control diet or diet containing pregnenolone-16α-carbonitrile (PCN; 800 ppm), 3-methylcholanthrene (3-MC; 200 ppm), or Aroclor 1254 (PCB; 100 ppm) for 7 days. Serum T(4), triiodothyronine (T(3)), and TSH concentrations, hepatic T(4)/T(3) glucuronidation, and thyroid histology and follicular cell proliferation were investigated. PCN, 3-MC, and PCB treatments decreased serum T(4), whereas serum T(3) was maintained in both Gunn and Wistar rats (except for PCB treatment). TSH was increased in Wistar and Gunn rats after PCN (130 and 277%) or PCB treatment (72 and 60%). T(4) glucuronidation in Wistar rats was increased after PCN (298%), 3-MC (85%), and PCB (450%), but was extremely low in Gunn rats, and unchanged after MEI. T(3) glucuronidation was increased after PCN (121%) or PCB (58%) in Wistar rats, but only PCN increased T(3) glucuronidation in Gunn rats (43%). PCN treatment induced thyroid morphological changes and increased follicular cell proliferation in both strains. These data demonstrate that T(4) glucuronidation cannot be increased in Ugt1a-deficient Gunn rats. Thus, the decrease in serum T(4), increase in TSH, and increase in thyroid cell proliferation after MEI are not dependent on increased T(4) glucuronidation, and cannot be attributed to Ugt1a enzymes.
Richardson
Terrilyn A
TA
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Klaassen
Curtis D
CD
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D020111:Chlorodiphenyl (54% Chlorine) / Q000633:toxicity*; D014453:Glucuronosyltransferase / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011285:Pregnenolone Carbonitrile / Q000633:toxicity*; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000187:drug effects / Q000201:enzymology; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000187:drug effects / Q000378:metabolism; D014284:Triiodothyronine / Q000097:blood; D000099148:UGT1A1 Enzyme
D020111:Chlorodiphenyl (54% Chlorine); D014453:Glucuronosyltransferase; D008748:Methylcholanthrene; D011285:Pregnenolone Carbonitrile; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme; C107611:UDP-glucuronosyltransferase, UGT1A7