title: Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin.
abstract: Nuclear receptor humanized mice models have been developed to predict regulation of drug metabolizing enzyme by xenobiotics. However, limited information is available concerning xenobiotic-induced regulation of drug metabolizing enzymes in multiple nuclear receptor humanized mice. The present study investigated the hepatic regulation of cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) in the pregnane X receptor (PXR) and the constitutive androstane receptor double humanized mice treated with rifampicin (RIF; 10mg/kg) for 4 days. RIF increased hepatic microsomal protein and total CYP contents, and CYP reductase activity in the humanized mice, but not in normal mice. Moreover, hepatic induction of Cyp2b10, Cyp2c, and Cyp3a11 were observed only in the RIF-treated humanized mice, suggesting that the humanized mice are sensitive to RIF with respect to the regulation of the hepatic CYP system. Hepatic UGT activities using estradiol, serotonin, and mefenamic acid, but not chenodeoxycholic acid as substrates, increased in the RIF-treated humanized mice, and the glucuronidation activities of estradiol and chenodeoxycholic acid increased in RIF-treated normal mice. These results raise the possibility that a PXR-independent mechanism may be involved in hepatic regulation of UGTs by RIF.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Hanyang University, Ansan, Gyeonggido 426-791 Republic of Korea.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address: sangkim@cnu.ac.kr.
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Bio-Evaluation Center, KRIBB, 685-1 Yangcheong-ri, Ochang-eup, Cheongwon-gun, Chungbuk 363-883, Republic of Korea. Electronic address: diatree@kribb.re.kr.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D000090702:Constitutive Androstane Receptor; D065701:Cytochrome P-450 CYP3A Inducers; D065693:Cytochrome P-450 Enzyme Inducers; D007527:Isoenzymes; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D014453:Glucuronosyltransferase; D012293:Rifampin
keywords: Cytochrome P450; Humanized mice; Nuclear receptor; Rifampicin; UDP-glucuronosyltransferase