1992 Fiscal Year Final Research Report Summary
Genetic factors of alcoholic liver disease and polymorphisms of cytochrome P4502E1.
| Project/Area Number |
03454232
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Gastroenterology
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| Research Institution | KANAZAWA MEDICAL UNIVERSITY |
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Principal Investigator |
TAKADA Akira KANAZAWA MEDICAL UNIVERSITY, MEDICINE, PROFESSOR., 医学部, 教授 (30064497)
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| Co-Investigator(Kenkyū-buntansha) |
TSUTSUMI Mikihiro KANAZAWA MEDICAL UNIVERSITY, MEDICINE, ASSISTANT PROFESSOR., 医学部, 講師 (00155425)
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| Project Period (FY) |
1991 – 1992
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| Keywords | Alcoholic liver disease / Cytochrome P4502E1 / Pathogenesis / Genetic polymorphisms / Messenger RNA / Genotyping / Enzyme induction / Ethanol metabolism |
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| Research Abstract |
Genotypes of cytochrome P4502E1 (P4502E1) were determined by the restriction fragment length polymorphisms technique in patients with alcoholic liver disease (ALD). DNA fragments of P4502E1 amplified by polymerase chain reactions were treated with 2 types of endonucleases, Rsa I and Pst I. The c1 gene of P4502E1 was digested with Rsa I, but not with Pst I, and the c2 gene was digested with Pst I, but not with Rsa I. Consequently, the genotypes of P4502E1 were separated into 3 types: type A which is homozygous for the c1 gene, type B which is heterozygous for the c1 and c2 genes and type C which is homozygous for the c2 gene.
In 31 patients with ALD, 29 (93.5%) were determined to have the type B genotype of P4502E1 and 2 (6.3%) the type C. Type A was not found in any patient with ALD. On the other hand, type A was found in all of the heavy drinkers without ALD. In healthy controls, type A was found in 63.3%. The difference in prevalence of genotypes between patients with ALD and healthy controls or heavy drinkers without ALD was significant statistically. These results indicate that the development of ALD is controlled genetically and that the genotype of P4502E1 is the most important determining factor in its development. Hepatic messenger RNA contents in type B were 3 times higher than in type A. These results also indicate that the transcriptional activity of the c2 gene is stronger than that of the c1 gene, even in human livers. These results lead to the conclusion that polymorphisms of the P4502E1 gene may be linked to development of ALD through enhancement of ethanol metabolism in the non-alcohol dehydrogenase pathway.
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