Chronic alcohol-induced liver injury and oxidant stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized cytochrome P4502E1 knock-in mice.
Chronic alcohol-induced liver injury and oxidant stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized cytochrome P4502E1 knock-in mice.
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DOI：
10.1016/j.freeradbiomed.2010.07.026
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发表时间：
2010-11-15
影响因子：
7.4
通讯作者：
Cederbaum, Arthur I.
中科院分区：
文献类型：
--
作者：
Lu, Yongke;Wu, Defeng;Wang, Xiaodong;Ward, Stephen C.;Cederbaum, Arthur I.
慢性乙醇诱导的肝损伤的主要途径是乙醇诱导的氧化应激。几种途径有助于乙醇诱导氧化应激的机制。虽然一些研究支持细胞色素P450 2 E1（CYP 2 E1）的作用，但其他研究则不支持。大多数先前的研究是在乙醇给药的胃内输注模型中进行的。有必要开发显著肝损伤的口服模型，并评估CYP 2 E1在此类模型中乙醇作用中的可能作用。我们在野生型（WT）小鼠、CYP 2 E1敲除（KO）小鼠和人源化CYP 2 E1敲入（KI）小鼠中评估了慢性乙醇诱导的肝损伤、脂肪变性和氧化应激，其中将人2 E1添加回小鼠2 E1缺陷的小鼠。WT小鼠和CYP 2 E1 KO和KI小鼠（均由Dr F. Gonzalez，NCI）喂食高脂肪Lieber-DeCarli乙醇液体饮食3周;成对喂食的对照接受葡萄糖。乙醇在WT小鼠中产生脂肪肝和氧化应激，但肝损伤（转氨酶，组织病理学）极轻微。乙醇诱导的脂肪变性和氧化应激在KO小鼠中减弱（无肝损伤），但在KI小鼠中恢复。乙醇喂养的KI小鼠产生了显著的肝损伤，转氨酶升高，坏死，1型胶原和平滑肌肌动蛋白水平升高。与WT小鼠中的小鼠2 E1水平相比，KI小鼠中的这种肝损伤与氧化应激升高和人CYP 2 E1水平升高相关。与其他组相比，在乙醇喂养的KI小鼠中观察到JNK的活化和Bcl-2和Bcl-XL水平的降低。WT和KI小鼠的脂肪肝与较低水平的PPAR α和酰基CoA氧化酶相关。在乙醇喂养的KO小鼠中未发现此类变化。这些结果表明，CYP 2 E1在乙醇诱导的脂肪肝和氧化应激中起主要作用。KO小鼠中CYP 2 E1的缺失负责脂肪变性和氧化应激的钝化，因为恢复CYP 2 E1恢复脂肪肝和氧化应激。此外，正是人CYP 2 E1恢复了乙醇的这些作用，这表明来自啮齿动物乙醇摄入模型和小鼠CYP 2 E1的脂肪肝和氧化应激结果可以外推至人乙醇摄入模型和人CYP 2 E1。
A major pathway for chronic ethanol-induced liver injury is ethanol-induced oxidant stress. Several pathways contribute to mechanisms by which ethanol induces oxidant stress. While some studies support a role for cytochrome P450 2E1 (CYP2E1), others do not. Most previous studies were conducted in the intragastric infusion model of ethanol administration. There is a need to develop oral models of significant liver injury and to evaluate the possible role of CYP2E1 in ethanol actions in such models. We evaluated chronic ethanol-induced liver injury, steatosis and oxidant stress in wild type (WT) mice, CYP2E1 knockout (KO) mice and in humanized CYP2E1 knockin (KI) mice, where the human 2E1 was added back to mice deficient in the mouse 2E1. WT mice and the CYP2E1 KO and KI mice (both provided by Dr F. Gonzalez, NCI) were fed a high fat Lieber-DeCarli ethanol liquid diet for 3 weeks; pair-fed controls received dextrose. Ethanol produced fatty liver and oxidant stress in WT mice but liver injury (transaminases, histopathology) was minimal. Ethanol-induced steatosis and oxidant stress was blunted in the KO mice (no liver injury) but restored in the KI mice. Signicant liver injury was produced in the ethanol-fed KI mice with elevated transaminases, necrosis, and increased levels of collagen type 1 and smooth muscle actin. This liver injury in the KI mice was associated with elevated oxidant stress and elevated levels of the human CYP2E1 compared to levels of the mouse 2E1 in WT mice. Activation of JNK and decreased levels of Bcl-2 and Bcl-XL were observed in the ethanol-fed KI mice compared to the other groups. Fatty liver in the WT and the KI mice was associated with lower levels of PPAR alpha and acyl CoA oxidase. No such changes were found in the ethanol-fed KO mice. These results show that CYP2E1 plays a major role in ethanol-induced fatty liver and oxidant stress. It is the absence of CYP2E1 in the KO mice responsible for the blunting of steatosis and oxidant stress since restoring the CYP2E1 restores the fatty liver and oxidant stress. Moreover, it is the human CYP2E1 which restores these effects of ethanol which suggests that results on fatty liver and oxidant stress from rodent models of ethanol intake and mouse CYP2E1 can be extrapolated to human models of ethanol intake and to human CYP2E1.
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影响因子：
25.7
作者：
Butura, Angelica;Nilsson, Kerstin;Ingelman-Sundberg, Magnus
通讯作者：
Ingelman-Sundberg, Magnus
影响因子：
6.1
作者：
DILUZIO, NR
通讯作者：
DILUZIO, NR
影响因子：
25.7
作者：
Järveläinen, HA;Fang, C;Lindros, KO
通讯作者：
Lindros, KO
DOI：
10.1152/ajpgi.90358.2008
发表时间：
2008-10-01
影响因子：
4.5
作者：
Ajmo, Joanne M.;Liang, Xiaomei;You, Min
通讯作者：
You, Min
影响因子：
3.9
作者：
Cheung, C;Yu, AM;Gonzalez, FJ
通讯作者：
Gonzalez, FJ