PII‐27

It has been well known that hepatic CYP expression widely varies in general population and large part of this variability may be attributed to genetic factors. Although the presence of genetic variations in CYP genes has been extensively explored, it is well agreed that the individual variation in CYP expression and activity cannot be expected solely from CYP genetic variations. Recent studies have revealed that hepatocyte nuclear factor‐4 alpha (HNF‐4A) is an essential transcription regulator of many CYPs such as CYP2D6, CYP3A4, etc. We hypothesized that the genetic variation of HNF‐4A may contribute to the individual variability of CYPs. In the present study, the genetic polymorphism of HNF‐4A was investigated in 50 Korean subjects through direct sequencing of all exons, exon‐intron boundaries, and promoter region of HNF‐4A gene. Twenty SNP, including two novel nonsynonymous SNPs in exon 2, were identified. One novel HNF‐4A variant was tested for its functional alteration by its trans‐activation activity of CYP2D6 promoter since this promoter contains functional DNA element for HNF‐4A binding. The variant showed the total loss of function to regulate CYP2D6 promoter activity. We also confirmed that the mutant HNF‐4A protein could not bind to CYP2D6 promoter region through EMSA experiment. The allelic frequency of this mutant HNF‐4A in Koreans was about 2%. Our results suggest that natural HNF‐4A variant may play a role in the interindividual variability of CYP2D6 expression. Clinical Pharmacology & Therapeutics (2005) 79 , P43–P43; doi: 10.1016/j.clpt.2005.12.152