Alcohol and Alcoholism Advance Access originally published online on January 14, 2009
Alcohol and Alcoholism 2009 44(3):261-266; doi:10.1093/alcalc/agn123
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A Promoter Polymorphism in the ALDH2 Gene Affects Its Basal and Acetaldehyde/Ethanol-Induced Gene Expression in Human Peripheral Blood Leukocytes and HepG2 Cells
1 Department of Hygiene, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640
2 Department of Forensic Medicine, The Jikei University School of Medicine, Tokyo 105-8461
3 Tokyo Medical Examiner's Office, Tokyo Metropolitan Government, Tokyo 122-0012, Japan
* Corresponding author: Department of Hygiene, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan. Tel: +81-76-265-2213; Fax: +81-76-234-4232; E-mail: saijohk{at}med.kanazawa-u.ac.jp
Received 14 July 2008; first review notified 6 October 2008; in revised form 11 December 2008; accepted 22 December 2008; advance access publication 14 January 2009
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Abstract |
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Aims: 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 (487Glu/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.