A promoter polymorphism in the ALDH2 gene affects its basal and acetaldehyde/ethanol-induced gene expression in human peripheral blood leukocytes and HepG2 cells.
OBJECTIVE
To assess the effect of the -360G/A polymorphism in the promoter region of the human aldehyde dehydrogenase-2 (ALDH2) gene on its transcription, basal and acetaldehyde/ethanol-induced gene expression was examined by in vivo and in vitro experiments.


METHODS
Human peripheral blood leukocytes were collected before and after alcohol ingestion (0.4 g/kg body weight) in 21 healthy young Japanese volunteers with a deficient phenotype of ALDH2 ((487)Glu/Lys), and the levels of ALDH2 mRNA were quantified by real-time RT-PCR. The transcriptional activity of the ALDH2 promoter was investigated by a reporter assay using HepG2 cells in the presence or absence of acetaldehyde/ethanol.


RESULTS
The basal level of ALDH2 mRNA was significantly higher in -360A heterozygous subjects than in -360G homozygous subjects. In all subjects, regardless of the genotype, ALDH2 mRNA increased following ethanol ingestion. The promoter activity of a reporter plasmid for -360G was significantly lower than that of a reporter plasmid for -360A. Exposure to acetaldehyde induced a significant increase in the transcriptional activity of the -360G reporter, but not the -360A reporter.


CONCLUSIONS
In vivo and in vitro experiments showed that the -360G allele has lower basal transcriptional activity than the -360A allele, whereas acetaldehyde/ethanol-induced gene expression, in general, seems to be more enhanced in individuals homozygous for the -360G allele than in those with the -360A allele. Thus, the promoter polymorphism may be involved in individual differences in acetaldehyde elimination.
Kimura
Yukiko
Y
Department of Hygiene, Kanazawa University Graduate School of Medical Science, Takara-machi, Kanazawa, Japan.
Nishimura
Fusae T
FT
Abe
Shuntaro
S
Fukunaga
Tatsushige
T
Tanii
Hideji
H
Saijoh
Kiyofumi
K
D000079:Acetaldehyde / Q000097:blood*; D000428:Alcohol Drinking / Q000097:blood / Q000235:genetics; D000444:Aldehyde Dehydrogenase / Q000097:blood* / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D045744:Cell Line, Tumor; D000431:Ethanol / Q000097:blood*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D055815:Young Adult
D000431:Ethanol; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde