Expression of Constitutive Androstane Receptor, Hepatic Nuclear Factor 4α, and P450 Oxidoreductase Genes Determines Interindividual Variability in Basal Expression and Activity of a Broad Scope of Xenobiotic Metabolism Genes in the Human Liver
- 18 June 2007
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 35 (9), 1700-1710
- https://doi.org/10.1124/dmd.107.016436
Abstract
Identification of genetic variation predictive of clearance rate of a wide variety of prescription drugs could lead to cost-effective personalized medicine. Here we identify regulatory genes whose variable expression level among individuals may have widespread effects upon clearance rate of a variety of drugs. Twenty liver samples with variable CYP3A activity were profiled for expression level and activity of xenobiotic metabolism genes as well as genes involved in the regulation thereof. Regulatory genes whose expression level accounted for the highest degree of collinearity among expression levels of xenobiotic metabolism genes were identified as possible master regulators of drug clearance rate. Significant linear correlations (p < 0.05) were identified among mRNA levels of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, MRP2, OATP2, P450 oxidoreductase (POR), and UDP-glucuronosyltranferase 1A1, suggesting that these xenobiotic metabolism genes are coregulated at the transcriptional level. Using partial regression analysis, constitutive androstane receptor (CAR) and hepatic nuclear factor 4α (HNF4α) were identified as the nuclear receptors whose expression levels are most strongly associated with expression of coregulated xenobiotic metabolism genes. POR expression level, which is also associated with CAR and HNF4α expression level, was found to be strongly associated with the activity of many cytochromes P450. Thus, interindividual variation in the expression level of CAR, HNF4α, and POR probably determines variation in expression and activity of a broad scope of xenobiotic metabolism genes and, accordingly, clearance rate of a variety of xenobiotics. Identification of polymorphisms in these candidate master regulator genes that account for their variable expression among individuals may yield readily detectable biomarkers that could serve as predictors of xenobiotic clearance rate.Keywords
This publication has 34 references indexed in Scilit:
- Biochemical analysis of mutations in P450 oxidoreductaseBiochemical Society Transactions, 2006
- Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor α, and the Coactivator Peroxisome Proliferator-activated Receptor γ Coactivator-1αPublished by Elsevier BV ,2006
- INVOLVEMENT OF HEPATOCYTE NUCLEAR FACTOR 4α IN THE DIFFERENT EXPRESSION LEVEL BETWEEN CYP2C9 AND CYP2C19 IN THE HUMAN LIVERPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2006
- Compendium of gene expression profiles comprising a baseline model of the human liver drug metabolism transcriptomeXenobiotica, 2006
- Human CYP2C8 Is Transcriptionally Regulated by the Nuclear Receptors Constitutive Androstane Receptor, Pregnane X Receptor, Glucocorticoid Receptor, and Hepatic Nuclear Factor 4αMolecular Pharmacology, 2005
- Transgenic Mice with a Hypomorphic NADPH-Cytochrome P450 Reductase Gene: Effects on Development, Reproduction, and Microsomal Cytochrome P450Journal of Pharmacology and Experimental Therapeutics, 2004
- Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship toCYP2B6Genotype and CAR (Constitutive Androstane Receptor) ExpressionJournal of Pharmacology and Experimental Therapeutics, 2003
- Identification of Constitutive Androstane Receptor and Glucocorticoid Receptor Binding Sites in the CYP2C19 PromoterPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2003
- Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesisNature Genetics, 2003
- Cytochrome P-450 mRNA Expression in Human Liver and Its Relationship with Enzyme ActivityArchives of Biochemistry and Biophysics, 2001