PT  - JOURNAL ARTICLE
AU  - Jie Gao
AU  - Zhao Wang
AU  - Gao-Ju Wang
AU  - Hong-Xin Zhang
AU  - Na Gao
AU  - Jie Wang
AU  - Cai-E. Wang
AU  - Zhao Chang
AU  - Yan Fang
AU  - Yun-Fei Zhang
AU  - Jun Zhou
AU  - Han Jin
AU  - Hai-Ling Qiao
TI  - Higher CYP2E1 Activity Correlates with Hepatocarcinogenesis Induced by Diethylnitrosamine
AID  - 10.1124/jpet.117.245555
DP  - 2018 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 398--407
VI  - 365
IP  - 2
4099  - http://jpet.aspetjournals.org/content/365/2/398.short
4100  - http://jpet.aspetjournals.org/content/365/2/398.full
SO  - J Pharmacol Exp Ther2018 May 01; 365
AB  - Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and the third most frequent cause of cancer death worldwide. Diethylnitrosamine (DEN) is one of the recognized risk factors for hepatocarcinogenesis likely due to CYP2E1-mediated metabolic activation. However, CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients has not been determined; the role of CYP2E1 activity, in particular CYP2E1 constitutive activity and CYP2E1 inhibited activity, with respect to the hepatocarcinogenesis induced by DEN is not yet clear. Herein, we determined CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients and found that CYP2E1-mediated DEN metabolic activity was significantly elevated with a 43.3% positive rate, and clinicopathologic parameters did not affect the activity. Then, using a Sprague-Dawley rat liver tumor model induced by DEN, the relationship between CYP2E1 constitutive/inhibited activity and hepatocarcinogenesis was explored. The results showed that the CYP2E1 constitutive activity was strongly correlated with tumor incidence and severity of liver tumorigenesis (nodule numbers and size), whereas inhibition of CYP2E1 activity decreased hepatocyte proliferation, liver injury, and liver carcinogenesis in the presence of DEN. In conclusion, the higher CYP2E1 activity would lead to an increased incidence of HCC as a result of CYP2E1-mediated DEN activation. Therefore, higher CYP2E1 activity might be a risk factor for HCC induced by DEN.