Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele

Abstract

These results indicate that acetaldehyde, rather than ethanol or acetate, is primarily responsible for the observed alcohol sensitivity reactions and suggest that substantially lower accumulation of blood acetaldehyde in the heterozygotes significantly reduces the aversion reaction to low amounts of alcohol that permits other biological as well as environmental factors to facilitate drinking and the according risk for the disease.

Distribution of Alcohol Related ALDH2 Genotypes among Six Ethnic Groups of Nepal

“…The occurrence of the ALDH2*2 allele in the ethnic groups will lead to the genetic adaptation in relation to feeding system along with environments. The findings of the research are consistent to other researches carried out elsewhere (Hsu et al 1985;Goedde et al 1992;Chen et al 1994;Peng et al 2007;Kim et al 2008;Ding et al 2010;Matsuo et al 2013).…”

“…Rare prevalence of ALDH2*2 allele in the Munda provides a clue of its genetic mixture in the past with other Caucasoid and other populations. In addition to this, the prevalence of the ALDH2*2 allele in Nepalese ethnic groups will protect them from the exposure to various alcohol-related diseases because of the protective nature of the ALDH2*2 allele against alcoholism (Hira et al 2013) This kind of protective mechanism of the ALDH2*2 allele against has already been reported, especially in East Asians (Chen et al 1999;Peng et al 2007). The occurrence of the ALDH2*2 allele in the ethnic groups will lead to the genetic adaptation in relation to feeding system along with environments.…”

Increased brain uptake and oxidation of acetate in heavy drinkers

“…Administration of ethanol to humans elevates blood acetate (6, 9, 10) from <0.1 mM to 1 to 2 mM within minutes of the start of the administration (11,12). Consumption of enough alcohol to achieve breath alcohol levels of even 50 mg% is sufficient for plasma acetate levels to approach 1-2 mM, beyond which the plasma acetate concentration does not rise (6,9,10,12,13).…”

Roles of defective ALDH2 polymorphism on liver protection and cancer development

“…According to Peng et al [28], ethanol administration caused a 50 % increase in heart rate and 'terrible feelings' in ALDH2*1/*2 subjects, commonly referred to as ''flushing syndrome'', whereas no change was observed in ALDH2*1/*1 subjects. Given such vulnerability to drinking alcohol, it is not surprising that individuals with the ALDH2*2 allele tend not to be habitual drinkers.…”

“…(the cofactor of ALDH2) by 150-fold compared to the wild type enzyme [27]. In fact, an ethanol challenge of Chinese volunteers was shown to elicit a 20-fold higher blood acetaldehyde level in the ALDH2*1/*2 subjects than in ALDH2*1/*1 subjects [28].…”