Gadolinium chloride blocks alcohol-dependent liver toxicity in rats treated chronically with intragastric alcohol despite the induction of CYP2E1
Gadolinium chloride blocks alcohol-dependent liver toxicity in rats treated chronically with intragastric alcohol despite the induction of CYP2E1
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DOI：
10.1124/mol.51.6.944
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发表时间：
1997-06-01
影响因子：
3.6
通讯作者：
Thurman, RG
中科院分区：
文献类型：
--
作者：
Koop, DR;Klopfenstein, B;Thurman, RG
肝脏CYP 2 E1在几种酒精给药模型中诱导，但仅在涉及连续胃内给予含乙醇、玉米油基高脂饲料的大鼠模型中观察到临床相关病理学。CYP 2 E1的水平与胃内喂养模型中的肝脏病理学程度相关，这导致了CYP 2 E1的自由基产生是病理学原因的假设。用氯化钆（GdCl 3）破坏枯否细胞可防止乙醇依赖性病理学的发展，并减少灌胃酒精喂养大鼠胆汁中出现的自由基的产生。如果CYP 2 E1的诱导和随后由酶形成的氧化剂物质是乙醇依赖性肝脏病理的原因，那么GdCl 3的保护作用可能是由于抑制CYP 2 E1的诱导。在目前的研究中，乙醇给药4周产生明显的脂肪变性，坏死和炎症，在对照组大鼠中未见。免疫化学分析显示，乙醇处理动物的微粒体中CYP 2 E1被诱导5- 6倍。对硝基苯酚和氯唑沙宗羟基化速率升高约3倍，与CYP 2 E1诱导一致。当GdCl 3与乙醇一起给药时，枯否细胞受体表达降低约80%，肝脏病理学显著降低，这证实了先前的研究。然而，在乙醇和GdCl 3处理的动物中，CYP 2 E1的诱导没有显著降低。CYP 2 E1升高约5倍，通过免疫印迹分析估计，对硝基苯酚和氯唑沙宗羟化率升高3- 4倍，乙醇+GdCl 3处理的大鼠。因此，这些结果清楚地分离诱导CYP 2 E1的乙醇胃内输注的产生早期酒精诱导的肝脏疾病。结论：Kupffer细胞而不是CYP 2 E1在酒精引起的肝细胞损伤的启动中起主要作用。
Hepatic CYP2E1 is induced in several models of alcohol administration, but clinically relevant pathology is only observed in rats in a model involving the continuous intragastric administration of an ethanol-containing, corn oil-based, high-fat diet. The level of CYP2E1 correlates with the degree of liver pathology in the intragastric feeding model, which leads to the hypothesis that radical production by CYP2E1 is responsible for the pathology. Destruction of the Kupffer cells with gadolinium chloride (GdCl3) prevented the development of ethanol-dependent pathology and decreased the production of radicals that appeared in the bile of intragastrically alcohol-fed rats. If the induction of CYP2E1 and subsequent formation of oxidant species by the enzyme is causative in the ethanol-dependent hepatic pathology, then protection by GdCl3 could be due an inhibition of CYP2E1 induction. In the current study, ethanol-administration for 4 wk produced marked steatosis, necrosis, and inflammation not seen in control rats. Immunochemically, CYP2E1 was induced 5- to 6-fold in microsomes from the ethanol-treated animals. Rates of p-nitrophenol and chlorzoxazone hydroxylation were elevated approximately 3-fold, consistent with CYP2E1 induction. When GdCl3 was administered with ethanol, there was a decrease of approximately 80% in Kupffer cell receptor expression, and there was a significant decrease in hepatic pathology, which confirms previous studies. However, in the ethanol and GdCl3-treated animals, there was no significant decrease in the induction of CYP2E1. CYP2E1 was elevated approximately 5-fold, as estimated by immunoblot analysis, and rates of p-nitrophenol and chlorzoxazone hydroxylation were elevated 3- to 4-fold in ethanol + GdCl3-treated rats. Thus, these results clearly dissociate the induction of CYP2E1 by intragastric infusion of ethanol from the generation of early alcohol-induced liver disease. It is concluded that Kupffer cells rather than CYP2E1 play the major role in the initiation of hepatocyte damage caused by alcohol.