Effects of Aldehyde Dehydrogenase-2 Genetic Polymorphisms on Metabolism of Structurally Different Aldehydes in Human Liver

Abstract

This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Genotype analysis of the aldehyde dehydrogenase (ALDH)-2 gene was performed using an improved simplified method, and effects of the genotype on the metabolism of a variety of aldehydes in different fractions of human liver cells were investigated. The effects of sex, aging, smoking, drinking alcohol, liver function, and various drugs on ALDH activity were also analyzed. Of the 39 subjects, eight were heterozygotes of the wild (ALDH2*1) and mutant (ALDH2*2) alleles, and the others were homozygotes of the wild allele. ALDH activity toward acetaldehyde in liver mitochondria from subjects with a mutant allele was less than 10% of that with two alleles of wild-type, and the activities toward formaldehyde, propionaldehyde, n-butyraldehyde, capronaldehyde, and heptaldehyde were also significantly lower in the ALDH2*1/*2 rather than ALDH2*1/*1 group. However, the metabolism of octylaldehyde, decylaldehyde, retinaldehyde, benzaldehyde, 3-hydroxybenzaldehyde, and 2,5-dihydroxybenzaldehyde was similar in the two genotypes. Changes in activity in the cytosolic fraction were similar to those in mitochondria. There was no significant difference in ALDH activity in microsomes between the two groups. Total activities of ALDH toward acetaldehyde and other shortchain aliphatic aldehydes in supernatant fractions of homogenized liver were affected in a manner similar to that in mitochondria. Our results suggest that the single nucleotide polymorphisms of the ALDH2 gene only alter the metabolism of aldehydes with a short aliphatic chain. Furthermore, sex, drinking alcohol, and smoking had little effect on ALDH activity, although the activity in elderly individuals tended to be lower albeit statistically insignificant.

Accumulated hippocampal formaldehyde induces age-dependent memory decline

“…Therefore, decrease of ADH3 activity could lead to formaldehyde accumulation in brains with aging. ALDH2 polymorphism, which can result in the low activity of ALDH2 (Wang et al 2008), is related to susceptibility to late-onset Alzheimer's disease (Wang et al 2002). Knockout of ALDH2 induces age-dependent neurodegeneration with accompanying memory loss (Ohsawa et al 2008).…”

Aldehyde dehydrogenase 2 (ALDH2) polymorphism gene and coronary artery disease risk: a meta-analysis

“…Individuals homozygous for the ALDH2*2 allele have an 18 times higher peak blood acetaldehyde levels, while levels in heterozygotes are 5-fold higher compared with *1*1homozygotes (Amamoto et al, 2002). The ALDH2 enzyme is responsible for the detoxification of aldehydes generated by alcohol consumption and lipid peroxidation, including 4-hydroxynonenal (Wang et al, 2002). A genetic variant that decreases ALDH2 activity, the ALDH2 polymorphism, is transmitted in an autosomal additive manner and is common in the Asian population.…”

Reproductive Toxicity of Ethylene Glycol Monoethyl Ether in Aldh2 Knockout Mice

“…ALDH2, one of the ALDH isozymes, is a major enzyme involved in the metabolism of many short chain aliphatic aldehydes including ethoxyacetic aldehyde 6,7) . This isozyme is known to be polymorphic in the Asian population, and subjects bearing one or two of the mutant alleles have very low or almost no activity of aldehyde metabolism 7,8) . Therefore, there may be some differences in the metabolic rates and metabolite profiles of EGEE in subjects with different genotypes, which might also be reflected in EGEE toxicity.…”