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Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin

Title
Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin
Author
김영미
Keywords
Nuclear receptor; Humanized mice; Rifampicin; Cytochrome P450; UDP-glucuronosyltransferase; PREGNANE-X-RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; DRUG-DRUG INTERACTIONS; LVER-MICROSOMES; HUMAN HEPATOCYTES; INDUCED TOXICITY; RAT-LIVER; IN-VITRO; METABOLISM; INDUCTION
Issue Date
2015-06
Publisher
ELSEVIER IRELAND LTD
Citation
TOXICOLOGY LETTERS, v. 235, No. 2, Page. 107-115
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-glucuronosyl-transferases (UGTs) in the pregnane X receptor (PXR) and the constitutive androstane receptor double humanized mice treated with rifampicin (RIF; 10 mg/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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
URI
http://www.sciencedirect.com/science/article/pii/S0378427415001186?via%3Dihubhttp://hdl.handle.net/20.500.11754/36724
ISSN
0378-4274; 1879-3169
DOI
10.1016/j.toxlet.2015.03.015
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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