Constitutive Androstane Receptor and Pregnane X Receptor Gene Expression in Human Liver: Interindividual Variability and Correlation with CYP2B6 mRNA Levels

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Abstract
The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) mediate the expression of mammalian cytochrome P450 (P450) 2B genes, including CYP2B6 in humans. Large interindividual differences exist in hepatic CYP2B6 expression, but the molecular basis for this variability is not well understood. In the present study, we developed real-time polymerase chain reaction methods to measure CYP2B6, CAR, and PXR mRNA expression and compared the levels in a panel of 12 individual human liver samples. The transcripts of CAR and CYP2B6 were present in all the samples analyzed, whereas those of PXR were detectable in all but one sample. A striking finding was the 240-fold interindividual variability in hepatic CAR mRNA levels, which was similar to the variability (278-fold) in CYP2B6 mRNA levels but greater than the 27-fold variability in PXR mRNA expression. Additional analysis revealed positive and statistically significant correlations between the mRNA levels of CAR and CYP2B6 (r2 = 0.63, p = 0.002), PXR and CYP2B6 (r2 = 0.75. p < 0.001), and CAR and PXR (r2 = 0.86,p < 0.001). In summary, substantial interindividual differences exist in hepatic CAR and, to a lesser extent, PXR gene expression. The variability in the abundance of these transcription factors may contribute to the large interindividual differences in CYP2B6 gene expression in human liver.

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