Effect of -361 G/A polymorphism of aldehyde dehydrogenase-2 gene on alcohol metabolism and its expression in human peripheral blood leukocytes.
The deficiency in activity of aldehyde dehydrogenase-2 (ALDH2), commonly found in Asians, is due to a mutation at position 487 in exon 12, encoded by the ALDH2*2 allele, which is a crucial factor for deficient ability to acetaldehyde (AcH) oxidation. In addition to this locus, polymorphism in -361 G/A mutation of this gene at 5'flanking region, commonly found in multi-racial populations, is one of the suggestive polymorphisms which may affect on the enzyme activity because it has been reported to affect on the transcriptional activity in hepatoma cells. We aimed to examine the individual differences in alcohol metabolism in Japanese population based on the genotypes of both ALDH2 exon 12 and -361 G/A promoter region. Following genotyping of 2 loci, subject groups based on the promoter genotype was defined as variant A carrier (A+; A/A and G/A) or not (A-; G/G). Under the condition with 0.4 g/kg body weight of alcohol ingestion, significant differences in AcH peak levels, that reached at 30 or 60 minutes in most subjects, was not detected between promoter A+ and A- groups both in exon 12 ALDH2*1/*1 and ALDH2*1/*2 subjects. Furthermore, we developed a real-time RT-PCR method to detect and quantitate the ALDH2 mRNA levels in easily accessible peripheral blood leukocytes (PBLs) to examine whether this promoter mutation affects on the amount of ALDH2 mRNA in normal human tissue at pre- and post-alcohol ingestion phase in ALDH2*1/*1 subjects. Significant increase of mRNA was observed only in A- group at 2 hours after alcohol ingestion. Maximal changing rates of mRNA in PBLs within 3 hours after alcohol intake were +48 % and +17 % in A and A' groups, respectively. These results suggest that the individual differences in ALDH2 enzyme activity may be intricately regulated by the common polymorphisms in these two loci in Asian populations.
Nishimura
Fusae T
FT
Department of Hygiene, Kanazawa University School of Medicine and Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8640.
Kimura
Yukiko
Y
Abe
Shuntaro
S
Fukunaga
Tatsushige
T
Saijoh
Kiyofumi
K
D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D044466:Asian People; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D007564:Japan; D007962:Leukocytes / Q000737:chemistry*; D008297:Male; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis
D012333:RNA, Messenger; D000431:Ethanol; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial