Morimoto M, Hagbjörk A L, Wan Y J, Fu P C, Clot P, Albano E, Ingelman-Sundberg M, French S W
Department of Pathology, Harbor-UCLA Medical Center, Torrance 90509, USA.
Hepatology. 1995 Jun;21(6):1610-7.
This study was done to determine if a relationship exists between CYP2E1 induction by ethanol, lipid peroxidation, and liver pathology in experimental alcohol-induced liver disease in the rat. Rats were fed ethanol with or without diallyl sulfide (DAS) or phenethyl isothiocyanate (PIC) intragastrically for 1 month. CYP2E1 induction by ethanol was correlated with lipid peroxidation, liver microsomal CYP2E1 hydroxylation of paranitrophenol, and the liver pathology score using the data from the PIC-fed rats. Some of the data from the ethanol and DAS-fed rats were not included here because they have been reported elsewhere. Microsomal CYP2E1 protein levels induction by ethanol was decreased by PIC ingestion. Similarly, PIC reduced the increase microsomal reduced form of nicotinamide-adenine dinucleotide (NADPH)-dependent lipid peroxidation and p-nitrophenol hydroxylase (PNPH) activity, induced by ethanol feeding. The lipid peroxidation was reduced to below control levels; however, the pathology score was partially but not significantly reduced by isothiocyanate feeding. CYP2E1 messenger RNA (mRNA) was decreased by both inhibitors of CYP2E1. Immunohistochemical staining of liver for CYP2E1 protein showed that the lobular distribution of the isozyme changed from the centrilobular to a diffuse pattern, with an increase in the periportal region when the CYP2E1 inhibitors were fed with ethanol, and that this change correlated with the change in the distribution of fat in the lobule. The data support the idea that there is a link between CYP2E1 induction by ethanol and the early phase of ethanol-induced liver injury in this rat model. This link may involve lipid peroxidation, but other factors related to CYP2E1 induction must also be involved.
本研究旨在确定在大鼠实验性酒精性肝病中，乙醇诱导CYP2E1、脂质过氧化与肝脏病理之间是否存在关联。大鼠通过胃内给予乙醇，同时添加或不添加二烯丙基硫醚（DAS）或苯乙基异硫氰酸酯（PIC），持续1个月。利用PIC喂养大鼠的数据，将乙醇诱导的CYP2E1与脂质过氧化、肝脏微粒体中CYP2E1对对硝基苯酚的羟基化作用以及肝脏病理评分进行关联分析。乙醇和DAS喂养大鼠的部分数据未包含在此处，因为它们已在其他地方报道过。摄入PIC可降低乙醇诱导的微粒体CYP2E1蛋白水平升高。同样，PIC可降低乙醇喂养诱导的微粒体中还原型烟酰胺腺嘌呤二核苷酸（NADPH）依赖性脂质过氧化增加以及对硝基苯酚羟化酶（PNPH）活性增加。脂质过氧化降低至对照水平以下；然而，异硫氰酸酯喂养可使病理评分部分降低，但未达到显著水平。两种CYP2E1抑制剂均可降低CYP2E1信使核糖核酸（mRNA）水平。肝脏CYP2E1蛋白的免疫组织化学染色显示，当CYP2E1抑制剂与乙醇同时给予时，同工酶的小叶分布从中央小叶型变为弥漫型，门周区域增加，且这种变化与小叶内脂肪分布的变化相关。这些数据支持了在该大鼠模型中，乙醇诱导CYP2E1与乙醇诱导的肝损伤早期阶段之间存在联系的观点。这种联系可能涉及脂质过氧化，但也必定涉及与CYP
