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.

通过限制性片段长度多态性技术测定酒精性肝病（ALD）患者的细胞色素P4502E1（P4502E1）基因型。将通过聚合酶链式反应扩增的 P4502E1 的 DNA 片段用 Rsa I 和 Pst I 两种核酸内切酶处理。P4502E1 的 c1 基因被 Rsa I 消化，但不能被 Pst I 消化，c2 基因被 Pst I 消化，但 Rsa I 则不然。因此，P4502E1 的基因型分为 3 种类型： A 型，与 Rsa I 纯合。 c1 基因，B 型为 c1 和 c2 基因杂合，C 型为 c2 基因纯合。在 31 名 ALD 患者中，29 名（93.5%）被确定为 P4502E1 和 2 的 B 型基因型（6.3 %) C 型。在任何 ALD 患者中均未发现 A 型。另一方面，在所有没有 ALD 的重度饮酒者中都发现了 A 型。在健康对照中，A 型占 63.3%。 ALD 患者与健康对照者或无 ALD 的重度饮酒者之间的基因型患病率差异具有统计学意义。这些结果表明ALD的发生是受基因控制的，P4502E1的基因型是其发生的最重要的决定因素。 B型的肝脏信使RNA含量比A型高3倍。这些结果也表明，即使在人类肝脏中，c2基因的转录活性也比c1基因更强。这些结果得出这样的结论：P4502E1 基因的多态性可能通过非酒精脱氢酶途径中乙醇代谢的增强与 ALD 的发生有关。