INVOLVEMENT OF HEPATOCYTE NUCLEAR FACTOR 4 IN THE DIFFERENT EXPRESSION LEVEL BETWEEN CYP2C9 AND CYP2C19 IN THE HUMAN LIVER

CYP2C9 and CYP2C19 are clinically important drug-metabolizing enzymes. The expression level of CYP2C9 is much higher than that of CYP2C19, although 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 P450 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 se-quences, 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 o