Molecular basis of difference in alcohol metabolism between Orientals and Caucasians

Abstract

SummaryThe human cytosol alcohol dehydrogenase(ADH) controlled by ADH2 locus is known to be polymorphic. Most Caucasians have the usual enzyme consisting of the usual ~1 subunit, while nearly 90~ of Orientals have the atypical /~2 subunit. At the physiological pH, the cytosol enzyme activity of the atypical liver is much higher than that of the typical liver. It has been suggested that a high frequency of acute alcohol intoxication among Orientals could be related to the rapid accumulation of acetaldehyde due to the atypical ADH. Human liver aldehyde dehydrogenase (ALDH) is also polymorphic. Virtually all Caucasians have two major isozymes, i.e., ALDH-1 and ALDH-2, while about 50~ of Orientals have only ALDH-1, missing ALDH-2 component. Since ALDH-2 has high affinity to acetaldehyde, the high incidence of alcohol sensitivity in Orientals could be related to the accumulation of acetaldehyde due to the lack of ALDH-2 component. The usual ADH homodimer ~1/71 and the atypical homodimer ~2/~2 were purified to homogeneity. The specific activity of the atypical enzyme was nearly three orders of magnitude higher than the usual enzyme at the physiological pH. The usual enzyme was rapidly inactivated by iodoacetate, indicating an existence of the "active site cysteine'" in the molecule. In contrast, the atypical enzyme was resistant against the iodoacetate inactivation. Peptide mapping analysis revealed that the active site cysteine in the usual ~1 subunit is replaced by histidine in the atypical 82 subunit. In the usual ~1~1 enzyme, like horse enzyme, the catalytic Zn is expected to link to the sensitive cysteine at position 47, histidine at position 67, and cysteine at presumably position 174, thus making up the active site. In contrast, the active site of the atypical ~2~2 enzyme is expected to consist of the catalytic Zn linked to histidine at position 47, histidine at position 67, and cysteine at position around 174. The functional abnormalities of the atypical enzyme can be correlated to its molecular abnormality. 55

Alcohol abuse and related factors in Asia

“…It has become evident that alcohol sensitivity plays an important role in the phenomenon (Wolff, 1972). Abundant evidence also suggests that a deficiency of low Km, mitochondrial aldehyde dehydrogenase isoenzyme (ALDH1) in East Asians, such as Taiwanese and Japanese, plays a crucial role (Goedde et al, 1983;Yin & Li, 1989;Yoshida, 1982). It has been demonstrated that ALDH1-deficient individuals metabolize blood aldehyde more slowly than non-deficient individuals after alcohol ingestion (Mizoi et al, 1979).…”

Molecular characterization of cDNA clones encoding the human alcohol dehydrogenase .BETA.1 and the evolutionary relationship to the other class I subunits .ALPHA. and .GAMMA..

“…Furthermore, genetic polymorphism at the ADH2 locus is suspected to have importance in determining the degree of susceptibility to fetal alcohol syndromes (Streissguth et al 1980), alcoholism (Li 1977), and chlorpropamide-induced alcohol sensitivity (Leslie and Pyke 1978) (for a review, see Yoshida 1982). With that in mind, we were interested in 1) comparing nucleotide sequences of published ADH2 for nucleotide diversity, 2) finding a probe which can detect restriction length polymorphisms associated with ADH2 and 3) determining a phylogenetic tree for the three class I human ADHs.…”