Received for publication May 1, 2007.
Revised June 13, 2007.
Accepted for publication June 14, 2007.

Expression of CAR, HNF4, and POR Genes Determine Interindividual Variability in Basal Expression and Activity of a Broad Scope of Xenobiotic Metabolism Genes in the Human Liver

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, POR, and UGT1A1, suggesting these xenobiotic metabolism genes are co-regulated at the transcriptional level. Utilizing partial regression analysis, CAR and HNF4 were identified as the nuclear receptors whose expression levels most strongly associated with expression of co-regulated xenobiotic metabolism genes. POR expression level, which also associated with CAR and HNF4 expression level, was found to be strongly associated with the activity of many CYP450s. Thus, interindividual variation in the expression level of CAR, HNF4, and POR likely 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 accounting for their variable expression among individuals may yield readily-detectable biomarkers that could serve as predictors of xenobiotic clearance rate.

Key words: CAR, CYP gene regulation, human genetics, NADPH cytochrome P450 reductase, nuclear receptors, pharmacogenetics, regulation of gene expression

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