Polymorphism
See Also
Description
ALDH2 is expressed in several human tissues with the highest levels found in liver. Screening of human cDNA libraries has revealed that ALDH2 transcripts are present in human liver, kidney, heart, stomach, colon, muscle, ovary, pancreas, lung, prostate, ear, eye, marrow, gall bladder, testis, thyroid, retina, adipose, adrenal gland, blood, brain, breast, placenta, uterus, B-cells, fetal brain, tonsil, foreskin, nervous normal and also in lung tumor, bladder tumor, nervous tumor.
Function
Conversion of aldehydes to acids via the reaction: ALDEHYDE + NAD + H2O = ACID + NADH
ALDH2 is one of 19 members of the human ALDH gene family of NAD(P)+-dependent enzymes (). ALDH2 is the principal enzyme involved in acetaldehyde oxidation at the physiological concentrations typically found when a person consumes alcohol. In addition to the aforementioned dehydrogenase activity, ALDH2 possesses an esterase activity () that catalyzes the hydrolysis of nitroglycerin to generate 1,2-glyceryl dinitrate (1,2-GDN) and nitrite (NO2�) (). A common polymorphism in exon 12, in which glutamate is replaced by lysine at position 504 (Glu504Lys), is known to essentially eliminate its dehydrogenase activity and therefore its ability to clear acetaldehyde in homozygotes and to decrease by approximately 94% the enzyme activity in heterozygotes (,). Worldwide, the Lys504 allele has the highest prevalence (30�50%) in Asian populations, including Chinese people (). ALDH2 is a tetramer, and 1 defective subunit is sufficient to render the entire enzyme inactive; thus, Glu504 homozygotes (ALDH2*1/1) exhibit normal enzymatic activity, Glu504/Lys504 heterozygotes (ALDH2*1/2) show approximately 6% of normal activity, and Lys504 homozygotes (ALDH2*2/2) show negligible activity toward acetaldehyde. The ALDH2*2 allele is thus inherited as an autosomal dominant trait (4,6,). This mutation has been considered as a protective factor against the development of alcoholism and may explain distinct alcohol drinking habits across various ethnic populations .
Discussion
One of the most studied polymorphism is a single base-pair mutation (1510 GÆA) in exon 12 of ALDH2 gene that causes an E487K substitution (ALDH2*2 allele), which results in catalytic inactivation of the enzyme. The ALDH2*2 allele is dominant negative and is responsible for acute alcohol intoxication due to accumulation of acetaldehyde. Facial flushing, nausea, dizziness and tachycardia characterize this alcohol intoxication. The ALDH2*2 allele is frequent in, but confined to Asian individuals, and it appears to be a determinant against alcoholism. On the other hand, alcohol-drinking individuals having the ALDH2*2 genotype are at substantially high risk of developing esophageal and upper aerodigestive tract cancers, head and neck cancers, colorectal cancer.
The common G-to-A polymorphism in exon 12 of ALDH2 — resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes — is associated with a lack of efficacy of sublingual GTN in Chinese subjects.()
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