The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference.
The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference.
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CYP2A5 在肝损伤和纤维化中的作用：化学特异性差异。
DOI：
10.1007/s00210-015-1172-8
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Hong F;Si C;Gao P;Cederbaum AI;Xiong H;Lu Y
四氯化碳（CCL 4）或硫代乙酰胺（TAA）诱导的肝损伤依赖于细胞色素P450 2E1（CYP 2E1）。CYP2A5可被TAA诱导，但不被CCL 4诱导。在本研究中，在野生型（WT）小鼠和CYP2A5敲除（cyp2a5 −/−）小鼠中以及作为比较的CYP2E1敲除（cyp2e1 −/−）小鼠中研究了包括CCL 4或TAA诱导的纤维化在内的肝损伤。急性和亚慢性肝损伤，包括纤维化，由CCL4和TAA在WT小鼠中诱导，而不是在cyp2e1 −/−小鼠中，证实了CYP2E1在CCL4和TAA肝毒性中不可或缺的作用。WT小鼠和cyp2a5 −/−小鼠出现了由单次注射CCL4诱导的相当的急性肝损伤以及亚慢性肝损伤，包括由一个月重复给予CCL4诱导的纤维化，表明CYP2A5不影响CCL4诱导的肝损伤和纤维化。然而，虽然200 mg/kg TAA诱导的急性肝损伤在WT小鼠和cyp2a5 −/−小鼠中相当，但75和100 mg/kg TAA诱导的肝损伤在cyp2a5 −/−小鼠中比WT小鼠中更严重。多次注射200 mg/kg TAA 1个月后，虽然WT小鼠和cyp2a5 −/−小鼠的血清转氨酶显示亚慢性肝损伤相当，但cyp2a5 −/−小鼠的肝纤维化比WT小鼠更严重。这些结果表明，虽然CCL4和TAA诱导的肝损伤和纤维化都是CYP2E1依赖性的，但在某些条件下，CYP2A5可能对TAA诱导的肝损伤和纤维化具有保护作用，但它不影响CCL4的肝毒性。
Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild type (WT) mice and CYP2A5 knockout (cyp2a5−/−) mice as well as in CYP2E1 knockout (cyp2e1−/−) mice as a comparison. Acute and sub-chronic liver injuries including fibrosis were induced by CCL4 and TAA in WT mice but not in cyp2e1−/− mice, confirming the indispensable role of CYP2E1 in CCL4 and TAA hepatotoxicity. WT mice and cyp2a5−/− mice developed comparable acute liver injury induced by a single injection of CCL4 as well as sub-chronic liver injury including fibrosis induced by one month of repeated administration of CCL4, suggesting that CYP2A5 does not affect CCL4-induced liver injury and fibrosis. However, while 200 mg/kg TAA-induced acute liver injury was comparable in WT mice and cyp2a5−/− mice, 75 and 100 mg/kg TAA-induced liver injury were more severe in cyp2a5−/− mice than those found in WT mice. After multiple injections with 200 mg/kg TAA for one month, while sub-chronic liver injury as indicated by serum aminotransferases was comparable in WT mice and cyp2a5−/− mice, liver fibrosis was more severe in cyp2a5−/− mice than that found in WT mice. These results suggest that while both CCL4- and TAA-induced liver injuries and fibrosis are CYP2E1 dependent, under some conditions, CYP2A5 may protect against TAA-induced liver injury and fibrosis, but it doesn’t affect CCL4 hepatotoxicity.