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Genetic factors of alcoholic liver disease and polymorphisms of cytochrome P4502E1.

酒精性肝病的遗传因素与细胞色素P4502E1多态性。

基本信息

批准号：
03454232
负责人：
TAKADA Akira
金额：
$ 3.9万
依托单位：
KANAZAWA MEDICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03454232/
关键词：
Alcoholic liver disease Cytochrome P4502E1 Pathogenesis Genetic polymorphisms Messenger RNA Genotyping Enzyme induction Ethanol metabolism messengerRNA P450II E1 アルコ-ル性肝障害 pーnitrophenol hydroxylas polymerase chain reaction 肝生検組織

项目摘要

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.

应用限制性片段长度多态性技术检测酒精性肝病（ALD）患者细胞色素P4502E1（P4502E1）基因型。用聚合酶链反应扩增P4502E1的DNA片段，用两种内切酶Rsa I和Pst I处理。P4502E1的c1基因被Rsa I消化，但不被Pst I消化，c2基因被Pst I消化，但不被Rsa I消化。31例ALD患者中，P4502E1基因B型29例（93.5%），C型2例（6.3%）。所有ALD患者均未发现A型。另一方面，在所有没有ALD的重度饮酒者中发现了A型。在健康对照组中，A型占63.3%。ALD患者与健康对照组或无ALD的重度饮酒者之间的基因型患病率差异有统计学意义。这些结果表明，ALD的发展是受遗传控制的，P4502E1基因型是其发展的最重要的决定因素。肝信使RNA含量B型比A型高3倍。这些结果还表明，即使在人类肝脏中，c2基因的转录活性也比c1基因强。这些结果导致的结论，P4502E1基因的多态性可能与ALD的发展，通过增强乙醇代谢的非乙醇脱氢酶途径。