Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity.
Hepatocyte nuclear factor-4 alpha (HNF4A) is an essential transcriptional regulator for many genes that are expressed preferentially in the liver. Among the important functions of the liver is drug metabolism in response to xenobiotic exposure. Recent studies have suggested that HNF4A regulates the expression of cytochrome P450 (CYP), including CYP2D6 and CYP3A4, which show large individual variations in their activities. To understand the genetic factors that influence individual CYP activities, a genetic variant of HNF4A and the effects of genetic variants of HNF4A on CYP activity were investigated. Here, we report the identification of a novel coding variant of HNF4A that influences CYP2D6 activity in humans. After direct sequencing, a polymorphism search revealed the HNF4A G60D variant in Koreans. This variant was unable to bind to the recognition site in the CYP2D6 promoter and therefore lacked the regulatory function for this gene. Human liver specimens with the heterozygous HNF4A G60D genotype showed a tendency toward lower levels of CYP2D6 activity than the wild-type genotype in the same genetic background of CYP2D6. Furthermore, human subjects with the HNF4A G60D genotype tended to have lower CYP2D6 activity than those with the wild-type HNF4A. The HNF4A G60D variant was detected at low frequency in Asian populations, including Koreans, Chinese, and Vietnamese, and was not found in Africans or Caucasians.


CONCLUSIONS
This is the first report to show that the genetic polymorphism of liver-enriched nuclear receptor HNF4A influences downstream CYP2D6 function in human subjects.
Lee
Sang Seop
SS
Pharmacogenimics Research Center, Inje University College of Medicine, Busanjin-gu, Busan, Korea.
Cha
Eun-Young
EY
Jung
Hyun-Ju
HJ
Shon
Ji-Hong
JH
Kim
Eun-Young
EY
Yeo
Chang-Woo
CW
Shin
Jae-Gook
JG
D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D001665:Binding Sites; D002460:Cell Line; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D005260:Female; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic; D014162:Transfection
D051557:Hepatocyte Nuclear Factor 4; D004247:DNA; D019389:Cytochrome P-450 CYP2D6