Received for publication January 19, 2006.
Revised March 9, 2006.
Accepted for publication March 10, 2006.

Involvement of hepatocyte nuclear factor 4 in the different expression level between CYP2C9 and CYP2C19 in the human liver

Abstract

Cytochrome P450 2C9 (CYP2C9) and CYP2C19 are clinically important drug-metabolizing enzymes. The expression level of CYP2C9 is much higher than that of CYP2C19, though the factor(s) responsible for the difference between the expression levels of these genes is still unclear. It has been reported that hepatocyte nuclear factor 4 (HNF4) plays an important role in regulation of the expression of liver-enriched genes, including CYP genes. Thus, we hypothesized that HNF4 contributes to the difference between the expression levels of these genes. Two direct repeat 1 (DR1) elements were located in both the CYP2C9 and CYP2C19 promoters. The upstream and downstream elements in these promoters had the same sequences, and HNF4 could bind to both elements in vitro. The transactivation levels of constructs containing two DR1 elements of the CYP2C9 promoter were increased by HNF4, whereas those of the CYP2C19 promoter were not increased. The introduction of mutations into either the upstream or downstream element in the CYP2C9 gene abolished the responsiveness to HNF4. We also examined whether HNF4 could bind to the promoter regions of the CYP2C9 and the CYP2C19 genes in vivo. The results of chromatin immunoprecipitation assays showed that HNF4 could bind to the promoter region of the CYP2C9 gene but not to that of the CYP2C19 promoter in the human liver. Taken together, our results suggest that HNF4 is a factor responsible for the difference between the expression levels of CYP2C9 and CYP2C19 in the human liver.

Key words: CYP gene regulation, CYP2C, cytochrome P450 isoforms, cytochrome P450 regulation, human CYP enzymes, nuclear receptors

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