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

应用限制性片段长度多态技术检测酒精性肝病(ALD)患者细胞色素P4502E1(P4502E1)的基因分型。聚合酶链式反应扩增的P4502E1的DNA片段分别用Rsa I和Pst I两种内切酶处理。P4502E1的c1基因用Rsa I酶切，Pst I不用Pst I酶切，c2基因用Pst I酶切而不用Rsa I酶切。P4502E1B型29例(93.5%)，C型2例(6.3%)，ALD患者均未发现A型。另一方面，在所有没有ALD的酗酒者中都发现了A型。在健康对照组中，A型占63.3%。ALD患者与健康对照组和无ALD的酗酒者之间的基因频率差异有统计学意义。提示ALD的发生受遗传控制，P4502E1基因是ALD发生的最重要的决定因素。B型的肝脏信使RNA含量是A型的3倍。这些结果也表明，c2基因的转录活性强于c1基因，即使在人的肝脏中也是如此。这些结果表明，P4502E1基因的多态性可能通过促进非酒精脱氢酶途径中的乙醇代谢而与ALD的发生有关。

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.