From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor
From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor
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从肝纤维化到肝癌：较高的细胞色素 P450 2E1 活性是潜在的危险因素
DOI：
10.1002/mc.22851
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发表时间：
2018-10-01
影响因子：
4.6
通讯作者：
Qiao, Hai-Ling
中科院分区：
文献类型：
--
作者：
Gao, Jie;Wang, Zhao;Qiao, Hai-Ling
肝纤维化是肝癌发生的重要易感因素。然而，只有少数肝纤维化会发展为肝细胞癌（HCC）。由于细胞色素P450 2E1 （CYP2E1）参与了许多已知环境毒物和前致癌物的代谢和激活，该酶可能在肝纤维化后的肝癌发生中发挥作用。在此，我们评估了较高的CYP2E1活性是否是肝纤维化导致肝癌发生的危险因素。测定了72例HCC患者的纤维化组织和59例对照者的正常肝组织中CYP2E1的活性，以及肝癌患者肝纤维化的严重程度。同样，采用二乙基亚硝胺诱导的大鼠肝癌发生模型，测定肝纤维化和肝癌发生阶段CYP2E1活性，探讨肝纤维化阶段CYP2E1活性与肝癌发生的相关性，研究抑制CYP2E1活性对肝癌发生的影响。结果显示，虽然CYP2E1活性在伴有潜在肝纤维化的HCC患者中升高，但肝纤维化的严重程度与CYP2E1活性无关。在大鼠肝癌发生模型中，出乎意料地发现，CYP2E1活性从肝纤维化到肝癌发生下降。然而，重要的是，CYP2E1活性较高的肝纤维化大鼠发生了更严重的HCC。此外，抑制CYP2E1活性可以降低大鼠HCC的发生和发展。综上所述，较高的CYP2E1活性可能是肝纤维化致肝癌的危险因素，这增加了筛查肝纤维化患者CYP2E1活性以更好地估计其肝癌发生风险的可能性。
Hepatofibrosis is an important susceptibility factor for hepatocarcinogenesis. However, only a handful of cases of hepatofibrosis will develop into hepatocellular carcinoma (HCC). As cytochrome P450 2E1 (CYP2E1) is involved in the metabolism and activation of many known environmental toxicants and procarcinogens, this enzyme may play a role in the development of hepatocarcinogenesis subsequent to hepatofibrosis. Herein, we evaluated whether higher CYP2E1 activity is a risk factor for the development of hepatocarcinogenesis from hepatofibrosis. CYP2E1 activity in fibrotic tissues from 72 HCC patients and in normal liver tissues from 59 control subjects was determined along with the severity of hepatofibrosis in hepatocarcinogenesis patients. Similarly, using a rat diethylnitrosamine‐induced hepatocarcinogenesis model, CYP2E1 activity at the hepatofibrosis and hepatocarcinogenesis stages was determined, the correlation between CYP2E1 activity at the hepatofibrosis stage and hepatocarcinogenesis was explored, and the impact of inhibition of CYP2E1 activity on hepatocarcinogenesis was studied. The results showed that while CYP2E1 activity in HCC patients with underlying hepatofibrosis was increased, the severity of hepatofibrosis did not correlate with CYP2E1 activity. In the rat hepatocarcinogenesis model, unexpectedly, CYP2E1 activity was found to decrease from hepatofibrosis to hepatocarcinogenesis. Importantly, however, hepatofibrotic rats with higher CYP2E1 activity developed a more severe form of HCC. Moreover, inhibition of CYP2E1 activity could decrease the occurrence and development of HCC in rats. In conclusion, higher CYP2E1 activity may be a risk factor for hepatocarcinogenesis from hepatofibrosis, which raises the possibility of screening patients with hepatofibrosis for CYP2E1 activity to better estimate their risk for hepatocarcinogenesis.