New molecular forms of human liver alcohol dehydrogenase: isolation and characterization of ADHIndianapolis.

Abstract

The biochemital determinants of alcoholism and genetic correlates for the variability in man's response to alcohol have remained obscure until recently. The identification of genetically determined isoenzymes of alcohol dehydrogenase with different catalytic properties may bear importantly upon this problem. New molecular forms of human liver alcohol dehydrogenase (ADH; alcohol:NAD+ Commun. 91, 1549Commun. 91, -1555. The distinguishing features of these specimens were (i) they showed activity optima for ethanol oxidation at both pH 7.0 and 10.0 and (ii) they formed electrophoretic-bands cathodic to the ,B isoenzyme. From such livers, three new ADH forms have now been iso a, one of which has a single pH optimum at 7.0 and two of which have dual optima at pH 7.0 and 10.0. These new forms were designated ADHlndianapolis forms 1,2, and 3, respectively. They can be differentiated from previously described ADH isoenzymes, including the so-called "atypical" isoenzyme, by their electrophoretic mobility, pH optima, and Km for ethanol (approxi-mately 60 mM at pH 7.5) Based upon the electrophoretic pattern of livers containing ADHirnii and the mobility of the three isolated molecular forms, ADAiLdianapolis may be the result of polymorphism at the ADH2 gene locus, which codes for the , subunit.Humans exhibit large individual differences in their rate of alcohol metabolism and in their physiological, psychological, and pathological response to ethanol consumption (1). The potential relationships between these phenomena and the remarkable variability and large number of alcohol dehydrogenase (ADH; alcohol:NAD+ oxidoreductase, EC 1.1.1.1) isoenzymes in human liver have been discussed (2). Such comparisons are of quite recent origin largely because a means for the isolation and characterization of the molecular properties of human ADH isoenzymes had not been available. Specific affinity chromatographic techniques for ADH isoenzyme purification (3, 4) and electrophoretic procedures capable of resolving hitherto unidentified molecular forms (5, 6) have improved the situation rapidly and significantly.A genetic modelt proposed some years ago (7) has thus far satisfactorily accounted for most variations in ADH isoenzymes observed in earlier studies. It did not encompass -r-ADH (2), however, which was discovered subsequent to the proposal of the model. Most recently, we discovered yet other ADH molecular forms in 16% of autopsy liver specimens from Indianapolis, IN (6), which also could not be classified according to that model. Characteristically these livers manifest two pH optima for ethanol oxidation at pH 7.0 and 10.0 and form electrophoretic bands cathodic to the f3,B isoenzyme (6).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 5784We have now isolated three of these new molecular forms from such liver specimens. One of them exhibits a single activity o...

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

“…It has a substantially higher V max and somewhat higher K m compared with b1. The b3 isozyme was first detected in liver extracts from African-Americans (Bosron et al 1980) because of its lower pH optimum than the other ADH isozymes. It has also been found in Southwest Native Americans.…”

Human alcohol dehydrogenase: structural differences between the beta and gamma subunits suggest parallel duplications in isoenzyme evolution and predominant expression of separate gene descendants in livers of different mammals.

“…Atypical 02-subunits have been differently reported from livers of Caucasians and Asians (12-lern and f2-Oriental) (9,10), but both of these 2 types are now known to be structurally identical (11,12), differing from typical (1 subunits by a single His/Arg exchange at position 47. Another type of ADH, ADHIndianapolis, is probably derived from a further variant of the ADH2 locus (13). Finally, two additional gene loci are likely to code for the more different ir-and X-isoenzymes (14)(15)(16).…”

A Brief History of Research on the Genetics of Alcohol and Other Drug Use Disorders

“…One such intermediate phenotype was associated with a decreased risk for AUDs but was unrelated to SUDs: an intense skin fl ush after drinking related to several variations in alcohol metabolizing enzymes that were associated with an enhanced sensitivity to alcohol. This phenomenon had been observed for centuries in Asian drinkers (Japanese, Chinese, and Koreans), and the enzymes involved were identifi ed in the 1970s (Bosron et al, 1980;von Wartburg, 1980). The second intermediate phenotype, one that related to an enhanced risk for both AUDs and SUDs, was the long-known association between substance-related problems and impulsive behaviors Schuckit et al, 1970;Slutske et al, 1998).…”