Polymorphism of alcohol dehydrogenase, alcohol and aldehyde dehydrogenase activities: Implication in alcoholic cirrhosis in white patients

Abstract

Two types of factors can theoretically modulate alcohol metabolism toward increased acetaldehyde production. These factors are the following: (a) individual, genetically determined isoenzymes with distinct catalytic properties, and (b) modifications of enzyme activity induced by alcohol itself or liver damage. To investigate the respective roles of these factors in white individuals, we studied the alcohol dehydrogenase phenotype, together with liver alcohol dehydrogenase and aldehyde dehydrogenase activities, in 161 patients. Patients with alcoholic cirrhosis (n = 31) were compared with three types of controls: patients with nonalcoholic cirrhosis (n = 25) and excessive (n = 62) and moderate drinkers (n = 43) without liver disease. No association between alcohol dehydrogenase-3 phenotype and alcoholic cirrhosis was found. The prevalence of atypical alcohol dehydrogenase in the four groups was less than 1%. Patients with cirrhosis, regardless of its cause, had significantly lower alcohol dehydrogenase activity than the patients without cirrhosis (p less than 0.05 and p less than 0.01 vs. excessive and moderate drinkers, respectively). Among the noncirrhotic patients, alcohol dehydrogenase activity was significantly lower in the excessive drinkers than in the moderate drinkers (p less than 0.001). Aldehyde dehydrogenase activity was not different between cirrhosis-free excessive and moderate drinkers; in contrast, compared with these two groups, it was significantly lower in the two cirrhosis groups (p less than 0.01). These results suggest that no phenotypic pattern of alcohol dehydrogenase-3 associated with alcoholic cirrhosis in white patients exists, that liver alcohol dehydrogenase activity falls as a consequence of both alcohol abuse and cirrhosis and that liver aldehyde dehydrogenase activity is unaffected by alcohol abuse and only falls after the onset of cirrhosis.

Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?

“…Thirty-three studies dealt with ADH2, 2 [2][3]6,8,11,[26][27][29][30][31][32]37,[39][40][41][42][43][44]46,47,51 and 20 studies in CYP2E1. 6,11,26,31,32,35,[41][42][43]54,[57][58][59][60][61][62][63][64][65]67 To investigate the association between any of the four loci considered and alcohol-induced liver disease, ten studies dealt with ADH2, 5,6,[31][32][33]35,44,49,50,…”

“…6,11,26,31,32,35,[41][42][43]54,[57][58][59][60][61][62][63][64][65]67 To investigate the association between any of the four loci considered and alcohol-induced liver disease, ten studies dealt with ADH2, 5,6,[31][32][33]35,44,49,50,57 For the determination of the genetic polymorphisms of ADH2, ADH3, CYP4502E1, Pst-I/Rsa-I, and ALDH2, validated genotyping methods were used in all studiesnamely, polymerase chain reaction and restriction of the polymerase chain reaction product with the enzyme corresponding to each polymorphism. In three studies, 45,49,50 the genetic polymorphisms of the two alcohol dehydrogenase loci (ADH2 and ADH3) were determined from the enzymatic phenotypes (i.e., by electrophoretic differentiation of the ADH isozymes and by measurements of the ADH enzymatic activity in homogenized liver biopsy specimens).…”

Genetic polymorphism of alcohol dehydrogenase in europeans: TheADH2*2 allele decreases the risk for alcoholism and is associated withADH3*1

“…However, the low prevalence of ADH2*2 in whites 3 has precluded until now the finding of a significant correlation between this allele and alcohol pathology in Europe, [28][29][30][31][32] although a relationship similar to that found in Asians has been recently reported for Jewish 33 and Australian 34 men. Moreover, except for some alcohol-related cancers, [35][36][37] no correlation 28,[30][31][32]38,39 or conclusive results 34,40,41 have been reported regarding the influence of the ADH3 gene on alcohol-related pathologies in whites. In the present report we have analyzed a large European sample with the objective of determining the distribution of the ADH alleles in different European countries and correlating the ADH polymorphism with alcoholism and alcohol-induced cirrhosis in whites.…”

Alcohol Dehydrogenase Type 3 (ADH3) and the Risk of Bladder Cancer

“…ADH exists in several forms and is grouped in three classes that contain 5 ADH types [10]. More ADH types have recently been discovered, but the class I alcohol dehydrogenases are the major enzymes in the first step of ethanol metabolism [11, 12].…”

“…More ADH types have recently been discovered, but the class I alcohol dehydrogenases are the major enzymes in the first step of ethanol metabolism [11, 12]. Class I isoenzymes are formed by the random association of α, β and γ polypeptide subunits which are the products of three genes, ADH1 through ADH3 , respectively [10]. Polymorphisms have been observed in two of these genes, resulting in the production of three different β subunits (β1, β2 and β3) and two different γ subunits (γ1 and γ2) [10].…”