Bardag-Gorce Fawzia, Wilson L, Nan Li, Li Jun, French Barbara A, Morgan Timothy R, Morgan Kengathevy, French Samuel W
Harbor UCLA Medical Center, L.A. Biomed, 1000 W. Carson Street, Torrance, CA 90502, USA.
Exp Mol Pathol. 2005 Jun;78(3):207-11. doi: 10.1016/j.yexmp.2005.01.006. Epub 2005 Mar 23.
Mallory body (MB) formation is a complex phenomenon seen in chronic liver disease. CYP2E1 may play a role in preventing MB formation since it is involved in the elimination of toxic drugs and chemicals. When mice were fed with diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) for 10 weeks, Mallory bodies (MBs) developed in the liver at the end of this period. When DDC feeding was combined with CMZ (an efficient in vivo CYP2E1 inhibitor), more MBs formed compared to DDC feeding alone. DDC was shown to be a suicide inhibitor of CYP2E1. The level of CYP2E1 protein in the liver was further reduced by the DDC and CMZ treatment when measured by Western blot. To test whether CYP2E1 reduced MB formation, CYP2E1 knockout mice and CYP2E1 overexpressed mice were fed with DDC or DDC and CMZ for 10 weeks. MB formation increased markedly in the liver of CYP2E1 knockout mice when fed with DDC only. CYP2E1 overexpressed mice showed an increase in MB formation when the mice were fed with the combination of DDC and CMZ where the amount of CYP2E1 was reduced to levels seen in wild type mice. It was concluded that CYP2E1 inhibits MB formation by increasing the rate of elimination of DDC and/or its toxic intermediates.
马洛里小体（MB）的形成是慢性肝病中一种复杂的现象。细胞色素P450 2E1（CYP2E1）可能在预防MB形成中发挥作用，因为它参与有毒药物和化学物质的清除。当给小鼠喂食二乙基-1,4-二氢-2,4,6-三甲基-3,5-吡啶二羧酸酯（DDC）10周时，在此期间结束时肝脏中出现了马洛里小体（MBs）。当DDC喂养与CMZ（一种有效的体内CYP2E1抑制剂）联合使用时，与单独的DDC喂养相比，形成了更多的MBs。DDC被证明是CYP2E1的自杀性抑制剂。通过蛋白质免疫印迹法检测，DDC和CMZ处理进一步降低了肝脏中CYP2E1蛋白的水平。为了测试CYP2E1是否减少MB的形成，给CYP2E1基因敲除小鼠和CYP2E1过表达小鼠喂食DDC或DDC与CMZ 10周。仅喂食DDC时，CYP2E1基因敲除小鼠肝脏中的MB形成明显增加。当给CYP2E1过表达小鼠喂食DDC和CMZ的组合时，MB形成增加，此时CYP2E1的量降低到野生型小鼠中的水平。得出的结论是，CYP2E1通过提高DDC和/或其有毒中间体的清除率来抑制MB的形成。
