CYP2E1 is not involved in early alcohol-induced liver injury
CYP2E1 is not involved in early alcohol-induced liver injury
复制标题
DOI：
10.1152/ajpgi.1999.277.6.g1259
复制
发表时间：
1999-12-01
影响因子：
4.5
通讯作者：
Thurman, RG
中科院分区：
文献类型：
--
作者：
Kono, H;Bradford, BU;Thurman, RG
大鼠持续胃肠道喂养是酒精性肝损伤（ALI）研究的重要进展。迄今为止，我们所了解的大部分都涉及抑制剂或营养操纵，这些可能并不特定。敲除技术避免了这些潜在的问题。因此，我们使用小鼠长期胃内插管来研究早期ALI。活性氧参与了早期ALI的发病机制，但其主要来源尚不清楚。细胞色素P-450（CYP）2E1主要在肝细胞中由乙醇诱导，可能是导致肝损伤的活性氧的来源之一。我们的目的是确定是否CYP2E1参与ALI通过调整肠内酒精（EA）喂养模型CYP2E1基因敲除（-/-）小鼠。雌性CYP2E1野生型（+/+）或-/-小鼠连续4周给予高脂流质饮食，乙醇或等热量麦芽糖糊精作为对照。所有小鼠的体重在4周内稳定增加，组间无显著差异。对未处理小鼠或接受EA 4周的小鼠急性乙醇给药后，CYP2E1 +/+和-/-小鼠之间的乙醇消除率也无差异。然而，EA刺激率1.4倍，在两组。在CYP2E1 +/+和-/-小鼠中，EA使血清天冬氨酸氨基转移酶水平升高3倍至对照组的相似水平。对照组肝组织学正常。相比之下，给予乙醇的小鼠出现轻度脂肪变性、轻度炎症和坏死;然而，CYP2E1 +/+和-/-组之间无差异。慢性EA在CYP2E1 +/+和-/-小鼠中以相同的程度诱导其他CYP3A、CYP2A12、CYP1A和CYP2B家族。此外，POBN自由基加合物在两组中也相似。本文提供的数据与以下假设一致，即来自CYP 2E1的氧化剂在小鼠早期ALI的机制中仅起很小的作用。此外，这种新的小鼠模型说明了基因敲除技术在ALI研究中的实用性。
The continuous intragastric enteral feeding protocol in the rat was a major development in alcohol-induced liver injury (ALI) research. Much of what has been learned to date involves inhibitors or nutritional manipulations that may not be specific. Knockout technology avoids these potential problems. Therefore, we used long-term intragastric cannulation in mice to study early ALI. Reactive oxygen species are involved in mechanisms of early ALI; however, their key source remains unclear. Cytochrome P-450 (CYP)2E1 is induced predominantly in hepatocytes by ethanol and could be one source of reactive oxygen species leading to liver injury. We aimed to determine if CYP2E1 was involved in ALI by adapting the enteral alcohol (EA) feeding model to CYP2E1 knockout (-/-) mice. Female CYP2E1 wild-type (+/+) or -/- mice were given a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. All mice gained weight steadily over 4 wk, and there were no significant differences between groups. There were also no differences in ethanol elimination rates between CYP2E1 +/+ and -/- mice after acute ethanol administration to naive mice or mice receiving EA for 4 wk. However, EA stimulated rates 1.4-fold in both groups. EA elevated serum aspartate aminotransferase levels threefold to similar levels over control in both CYP2E1 +/+ and -/- mice. Liver histology was normal in control groups. In contrast, mice given ethanol developed mild steatosis, slight inflammation, and necrosis; however, there were no differences between the CYP2E1 +/+ and -/- groups. Chronic EA induced other CYP families (CYP3A, CYP2A12, CYP1A, and CYP2B) to the same extent in CYP2E1 +/+ and -/- mice. Furthermore, POBN radical adducts were also similar in both groups. Data presented here are consistent with the hypothesis that oxidants from CYP2E1 play only a small role in mechanisms of early ALI in mice. Moreover, this new mouse model illustrates the utility of knockout technology in ALI research.