Increase in rat liver UDP-glucuronosyltransferase mRNA by microsomal enzyme inducers that enhance thyroid hormone glucuronidation.
Treatment of rats with the microsomal enzyme inducers pregnenolone-16alpha-carbonitrile (PCN), 3-methylcholanthrene (3-MC), and Aroclor 1254 [PCB (polychlorinated biphenyl)] has been shown to decrease circulating levels of thyroid hormones as well as increase microsomal glucuronidation of thyroxine (T(4)). In addition, PCN increases triiodothyronine (T(3)) uridine diphosphate glucuronosyltransferase (UGT) activity. Members of the UGT1A family are believed to glucuronidate T(4), specifically UGT1A1 and UGT1A6, whereas the UGT2 family is believed to glucuronidate T(3), namely UGT2B2. The purpose of this study was to determine whether the aforementioned microsomal enzyme inducers increase the mRNAs that encode these and other UGT enzymes in rat liver. Male Sprague-Dawley rats were fed a control diet or a diet containing PCN (1000 ppm), 3-MC (250 ppm), or PCB (100 ppm) for 7 days, at which time livers were collected. Increases in mRNA were detected by QuantiGene branched DNA signal amplification. A 3-fold increase in UGT1A1 mRNA was produced by PCN in addition to increases in UGT1A2 (4-fold) and UGT1A5 (2-fold) mRNA. PCN affected neither UGT2B2 nor any other UGT2B mRNA level. 3-MC and PCB increased UGT1A6 mRNA 6- and 4-fold, respectively. 3-MC and PCB each increased UGT1A7 mRNA 4-fold but did not significantly increase any other UGT mRNAs. These findings suggest that PCN enhances T(4) UGT activity by increased expression of UGT1A1 and that 3-MC and PCB enhance T(4) UGT activity by increased expression of UGT1A6. These findings also suggest that increased T(3) UGT activity produced by PCN is due to a mechanism other than increased transcription of UGT2B2, possibly increased UGT2B2 protein or induction of another UGT enzyme.
Vansell
Nichole R
NR
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7417, USA.
Klaassen
Curtis D
CD
D000818:Animals; D015152:Blotting, Northern; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology*; D004587:Electrophoresis, Agar Gel; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology*; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013963:Thyroid Hormones / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000378:metabolism
D007527:Isoenzymes; D012333:RNA, Messenger; D013963:Thyroid Hormones; D014284:Triiodothyronine; D020111:Chlorodiphenyl (54% Chlorine); D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D014453:Glucuronosyltransferase; D013974:Thyroxine