Alcohol reaction and alcohol metabolism in Chinese subjects with different allelotypes of alcohol metabolic genes

• Main Authors: Peng Giia-Sheun, 彭家勛
• Other Authors: Yin Shih-Jiun
• Format: Others
• Language: zh-TW
• Published: 1998
• Online Access: http://ndltd.ncl.edu.tw/handle/73125652367873962185

博士 === 國防醫學院 === 醫學科學研究所 === 87 === Abstract Previous molecular genetic studies have indicated that the development of alcoholism in East Asian societies can be protected against by the variant high activity subunit-encoding ADH2*2 and the variant low activity subunit-encoding ALDH2*2 alleles. Homozygous ALDH2*2/*2 and heterozygous ALDH2*1/*2 appeared to fully and partially alcohol-rejecting gene statuses, respectively. To investigate possible pathophysiologic mechanisms underlying this pharmacogenetic uniqueness in East Asian populations, ethanol metabolism, cardiovascular hemodynamic and neuroendocrine changes, as well as subjective feelings were measured in subjects with different ADH and ALDH genotypes after ingestion of differing doses of ethanol during a period up to 240 min. Following a low dose of ethanol (0.2 g/kg body weight), homozygous ALDH2*2/*2 subjects exhibited marked elevation of blood acetaldehyde levels, manifested with persistently significant increases in heart beat, cardiac output, and blood flow rate of the common carotid, internal/external carotid and facial arteries; persistently significant decreases in diastolic pressure, systemic vascular resistance, and resistance index of the common carotid, external carotid and facial arteries; matched by significant andpersistent subjective sensation of facial warming, tachycardia and overall terrible feelings.After challenge with a moderate dose of ethanol (0.5 g/kg), heterozygous ALDH2*1/*2 subjects displayed elevated blood acetaldehyde levels, which were comparable to those observed in the homozygous ALDH2*2/*2 genotypes following a low dose of 0.2 g/kg ethanol, and also the similar cardiovascular alterations as well as subjective sensations similar to those seen in the ALDH2*2/*2 homozygotes. Following a low-to-moderate dose of ethanol (0.3 g/kg), no significant differences in the ethanol metabolism, heart beat and facial capillary flow rate were found for the three ADH2 genotype subjects while their ALDH2 genotype was controlled. Under this low-to-moderate dose challenge, ALDH2*1/*2 subjects, regardless of the ADH2 genotypes, exhibited significantly higher blood acetaldehyde levels, faster heart beat and facial capillary flow rate than did the ALDH2*1/*1 subjects. Changes in plasma levels of triiodothyronine, thyroxine and thyroid stimulating hormone were found no significant association with the ADH/ALDHgenotypes after ingestion of 0.3 g/kg ethanol. However, ALDH2*1/*2 subjects exhibited persistently significant higher levels of plasma prolactin and cortisol than did the ALDH2*1/*1 genotypes. Plasma adrenocorticotropic hormone levels also showed an increasing trend in the ALDH2*1/*2 subjects. The results suggest that full protection against developing alcoholism by homozygosity of the variant ALDH2*2 allele can be explained by low-dose alcohol hypersensitivity accompanied by a prolonged and large accumulation of acetaldehyde in blood which deters those individuals from drinking alcoholic beverage, and that partial protection against alcoholism by the gene status of ALDH2*1/*2 heterozygosity can attain through deliberate moderation in alcohol consumption due to unpleasant reaction. The reason forprotective role of the variant ADH2*2 allele is unclear in the present study, although it appeared no mainly through the involvement of blood acetaldehyde build up after ingestion of ethanol as did the variant ALDH2*2. Following challenge with a low-to-moderate dose of 0.3 g/kg ethanol, elevation of plasma prolactin and cortisol levels in the ALDH2*1/*2 genotypes may be due to a direct action of blood acetaldehyde upon pituitary gland, resulting in releasing of the stress-related hormones.