Differences in the isozymes involved in alcohol metabolism between caucasians and orientals

Acute alcohol intoxication is far more commonly observed in Orientals than Caucasians. The human liver contains several cytosolic and microsomal ADHs. One of the major cytosolic ADH isozymes controlled by a gene at the ADH2 locus differs between Caucasians and Orientals. Most Caucasians have the usual enzyme consisting of usual beta 1 subunit, while nearly 90% of Orientals have the atypical enzyme consisting of the atypical beta 2 subunit. The specific activity of the atypical enzyme is several times higher at pH 10 and nearly 100 times higher at physiologic pH than the usual enzyme. Km values for ethanol, NAD, acetaldehyde, and NADH are several times higher for the atypical enzyme than for the usual enzyme. The usual enzyme is rapidly inactivated by iodoacetate, indicating the existence of an "active-site cysteine" in the molecule. In contrast, the atypical enzyme is resistant to iodoacetate inactivation. Peptide mapping analysis revealed that the active site Cys in the usual beta 1 subunit is replaced by His in the atypical beta 2 subunit. A remarkable structural homology exists at the active site of horse and human enzymes. In the usual beta 1 beta 1 enzyme, as in the horse enzyme, the catalytic Zn is expected to link to the sensitive Cys at position 47, His at position 67, and Cys (presumably) at position 174, thus forming the active site. In contrast, the active site of the atypical beta 2 beta 2 enzyme is expected to consist of the catalytic Zn linked to His at position 47, His at position 67, and Cys (presumably) at position 174. The resistance of the atypical beta 2 beta 2 to inactivation by iodoacetate is a direct consequence of the replacement of the sensitive Cys at position 47 by His. Liver ALDH components also differ between Caucasians and Orientals. Virtually all Caucasians have two major ALDH isozymes, ALDH1 and ALDH2, while approximately 50% of Orientals have only the ALDH1 isozyme (cytosolic) missing ALDH2 isozyme (presumably mitochondrial). ALDH1 consists of four subunits with a molecular weight of 56,500, and ALDH2 consists of four subunits with a molecular weight of 52,600. The two isozymes do not share any common subunit. Examination of liver extracts by two-dimensional crossed immunoelectrophoresis revealed that an atypical Oriental liver with no ALDH2 isozyme contained an enzymatically inactive but immunologically cross-reactive material corresponding to ALDH2, besides the active ALDH1 isozyme.(ABSTRACT TRUNCATED AT 400 WORDS)