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Vol. 31, Issue 1, 7-10, January 2003
Faculty of Pharmaceutical Sciences, 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.
The University of British
Columbia,
Vancouver, British Columbia, Canada
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