Lu Yongke, Cederbaum Arthur I
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Hepatology. 2006 Jul;44(1):263-74. doi: 10.1002/hep.21241.
The mechanisms by which alcohol causes liver injury are still not certain. Either LPS or CYP2E1 are considered independent risk factors involved in alcoholic liver disease, but mutual relationships or interactions between them are unknown. In the present study, the possible synergistic action of CYP2E1 and LPS in liver injury was investigated by evaluating the effects of pyrazole (inducer of CYP2E1), Chlormethiazole (CMZ), an inhibitor of CYP2E1, and CYP2E1-knockout mice. Mice were injected with pyrazole (150 mg/kg, ip) daily for 2 days, followed by LPS injection (4 mg/kg, ip). CMZ (50mg/kg, ip) was administered 15 h before and 30 min after LPS treatment, respectively. LPS-induced liver injury was enhanced by pyrazole, as indicated by pathological changes and increases in ALT and AST, and positive TUNEL staining. LPS-induced oxidative stress was also enhanced by pyrazole as indicated by increases in 4-hydroxy-2-nonenal and 3-nitrotyrosine adduct formation. CMZ protected against the pyrazole enhanced LPS liver injury and oxidative stress. CYP2E1 but also CYP2A5 were increased by the pyrazole/LPS treatment. CMZ decreased the elevated CYP2E1 activity by 90%, but CYP2A5 activity was also lowered (30%-50%). CYP2E1-knockout mice exhibited only minor liver injury after treatment with pyrazole/LPS, but wild-type mice exhibited severe liver injury. While no CYP2E1 was present in the CYP2E1 knockout mice, CYP2A5 activity was also lower. In conclusion, induction of CYP2E1 plays an important role in the enhancement of LPS liver injury by pyrazole, but some contribution by CYP2A5 cannot be excluded.
酒精导致肝损伤的机制仍不明确。脂多糖（LPS）和细胞色素P450 2E1（CYP2E1）均被视为酒精性肝病的独立危险因素，但它们之间的相互关系或相互作用尚不清楚。在本研究中，通过评估吡唑（CYP2E1诱导剂）、氯美噻唑（CMZ，CYP2E1抑制剂）和CYP2E1基因敲除小鼠的作用，研究了CYP2E1和LPS在肝损伤中可能的协同作用。小鼠每天腹腔注射吡唑（150mg/kg），连续注射2天，随后腹腔注射LPS（4mg/kg）。CMZ（50mg/kg，腹腔注射）分别在LPS处理前15小时和处理后30分钟给药。如病理变化、谷丙转氨酶（ALT）和谷草转氨酶（AST）升高以及TUNEL染色阳性所示，吡唑增强了LPS诱导的肝损伤。如4-羟基壬烯醛和3-硝基酪氨酸加合物形成增加所示，吡唑也增强了LPS诱导的氧化应激。CMZ可预防吡唑增强的LPS肝损伤和氧化应激。吡唑/LPS处理可使CYP2E1以及细胞色素P450 2A5（CYP2A5）增加。CMZ使升高的CYP2E1活性降低了90%，但CYP2A5活性也有所降低（30%-50%）。CYP2E1基因敲除小鼠在接受吡唑/LPS处理后仅表现出轻微肝损伤，而野生型小鼠则表现出严重肝损伤。虽然CYP2E1基因敲除小鼠中不存在CYP2E1，但CYP2A5活性也较低。总之，CYP2E1的诱导在吡唑增强LPS肝损伤中起重要作用，但不能排除CYP2A5的一定作用。
