Nuclear receptor, pregname X receptor, is required for induction of UDP-glucuronosyltranferases in mouse liver by pregnenolone-16 alpha-carbonitrile.
The aim of this study was to determine the role of pregnane X receptor (PXR) in the induction of UDP-glucuronosyltransferases (UGTs) by pregnenolone-16 alpha-carbonitrile (PCN). Four- to six-month-old male wild-type and PXR-null mice received control or PCN-treated (1500 ppm) diet for 21 days. On day 22, livers were taken to prepare microsomes and total RNA to determine UGT activity and mRNA levels, respectively. In wild-type mice, PCN treatment significantly increased UGT activities toward bilirubin, 1-naphthol, chloramphenicol, thyroxine, and triiodothyronine. On control diet, the UGT activities toward the above substrates (except for 1-naphthol) in the PXR-null mice were significantly higher than those of wild-type mice. However, UGT activities in PXR-null mice were not increased by PCN. In agreement with the above findings, mRNA levels of mouse Ugt1a1 and Ugt1a9, which are involved in the glucuronidation of bilirubin and phenolic compounds, were increased about 100% in wild-type mice following PCN treatment, whereas the expression of Ugt1a2, 1a6, and 2b5 was not affected. In contrast, PCN treatment had no effect on the mRNA levels of these UGTs in PXR-null mice. Taken together, these results indicate that PCN treatment induces glucuronidation in mouse liver, and that PXR regulates constitutive and PCN-inducible expression of some UGTs.
Chen
Chuan
C
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Staudinger
Jeff L
JL
Klaassen
Curtis D
CD
D000284:Administration, Oral; D000818:Animals; D001663:Bilirubin / Q000737:chemistry / Q000378:metabolism; D002701:Chloramphenicol / Q000737:chemistry / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005502:Food; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009284:Naphthols / Q000737:chemistry / Q000378:metabolism; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000737:chemistry / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D013974:Thyroxine / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014284:Triiodothyronine / Q000737:chemistry / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D009284:Naphthols; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014284:Triiodothyronine; D011285:Pregnenolone Carbonitrile; D002701:Chloramphenicol; D014453:Glucuronosyltransferase; D013974:Thyroxine; D001663:Bilirubin