Genotypes of Alcohol‐Metabolizing Enzymes in Relation to Alcoholic Chronic Pancreatitis in Japan

Abstract

Long-term consumption of large amounts of alcohol is the main cause of chronic pancreatitis. All heavy drinkers, however, do not contract chronic pancreatitis. Although genetic predisposition to alcoholism and alcoholic liver disease has been reported, genetic susceptibility to alcoholic pancreatitis is still a matter of debate. To determine the relation between genotypes of alcohol-metabolizing enzymes and chronic alcoholic pancreatitis, we examined genotype patterns of aldehyde dehydrogenase 2 (ALDH 2), alcohol dehydrogenase 2 (ADH 2) and cytochrome P-4502E1 (CYP2E1) in 54 patients with chronic alcoholic pancreatitis who were diagnosed in general hospitals in all over Japan and compared with those in 30 patients with chronic nonalcoholic pancreatitis or in 46 alcoholics with normal pancreatic function. There were no significant differences in the distribution of genotypes of ALDH 2 and CYP2E1 among those three groups. As for the ADH 2 genotype, distribution of 2(1)/2(1), 2(1)/2(2), and 2(2)/2(2) was 35%, 30%, and 35% in alcoholics with normal pancreatic function; 4%, 39%, and 57% in the chronic alcoholic pancreatitis group; and 0%, 50%, and 50% in the chronic nonalcoholic pancreatitis group, respectively. The frequency of ADH 2(2) allele was significantly higher in the chronic alcoholic pancreatitis group, compared with alcoholics with normal pancreatic function; but, it was not significantly different from that in the chronic nonalcoholic pancreatitis group. We also examined the relation between pancreatic fibrosis or pancreatitis histologically diagnosed and genotypes of alcohol-metabolizing enzymes in alcoholic autopsy cases. Twenty of 31 cases showed moderate or severe pancreatic fibrosis and showed intralobular + interlobular fibrosis, which is characteristic in alcoholic pancreatitis or intralobular fibrosis. ADH 2(2) allele tended to show a high frequency in the intralobular + interlobular fibrosis group, compared with that in the intralobular fibrosis group (75.0% vs. 41.7%, p < 0.1). The chronic pancreatitis group had a significantly higher frequency of the ADH 2(2) allele than that in cases without such findings (87.5% vs. 58.7%, p < 0.05). However, the ALDH 2 and CYP2E1 genotypes showed no significant relation to the findings of pancreatic fibrosis or histological pancreatitis. These data suggest that the risk of chronic alcoholic pancreatitis diagnosed clinically and pathologically seems to be associated with the ADH 2(2) allele in the genotypes of alcohol-metabolizing enzymes.

The Role of Acetaldehyde in the Actions of Alcohol (Update 2000)

“…Thus, the rate of AcH production (i.e., the rate of ethanol oxidation) that has been shown to be significant in pancreatic acinar cells (Haber et al, 1998) should affect the development of alcoholic pancreatitis. This hypothesis is supported by human data, according to which alcoholic pancreatitis has been associated with ADH3*1 alleles in white subjects (Couzigou et al, 1991;Day et al, 1991) and ADH2*2 alleles in Asians (Chao et al, 1997;Matsumoto et al, 1996), but not with the ALDH2 polymorphism (Chao et al, 1997;Maruyama et al, 1999;Matsumoto et al, 1996).…”

The Genetics of Alcoholism in Polynesians: Alcohol and Aldehyde Dehydrogenase Genotypes in Young Men

“…These include upper gastrointestinal tract cancers (Coutelle et al, 1997;Tanabe et al, 1999;Väkeväinen et al, 2000), cirrhosis (Poupon et al, 1992;Yamauchi et al, 1995), and pancreatitis (Maruyama et al, 1999). Of particular interest to New Zealand researchers are a group of such studies that have been conducted with aboriginal tribes from Taiwan (Chen et al, 1997;Cheng and Chen, 1995;Thomasson et al, 1994).…”

Genetic Polymorphisms in Alcoholic Pancreatitis

“…While Kimura et al [58] concluded that genetic polymorphisms of the ALDH2 gene infl uence the risk of developing alcoholic pancreatitis (in Japanese patients), this was not confi rmed by Maruyama et al [60] in Japanese and by Frenzer et al [59] in Caucasian patients.…”

“…A study from Taiwan published by Chao et al [57] hypothesized later on that there might be an association between the ADH2*2 gene and (acute) alcoholic pancreatitis. However, the data published for patients with chronic alcoholic pancreatitis are not conclusive: No correlation was found between ADH2 polymorphisms and chronic pancreatitis in Japanese patients by Kimura et al [58] , and in 71 Australian patients (of European origin) by Frenzer et al [59] , while an elevated risk for chronic alcoholic pancreatitis for different genotypes of ADH2 was demonstrated by Maruyama et al [60] . In conclusion, further studies are needed to clarify these discrepancies, but these polymorphisms do not appear to be the key cofactors for alcoholic pancreatitis.…”