Oncotarget

Research Papers: Gerotarget (Focus on Aging):

High CYP2E1 activity correlates with hepatofibrogenesis induced by nitrosamines

Jie Gao, Gao-Ju Wang, Zhao Wang, Na Gao, Jing Li, Yun-Fei Zhang, Jun Zhou, Hong-Xin Zhang, Qiang Wen, Han Jin and Hai-Ling Qiao _

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Oncotarget. 2017; 8:112199-112210. https://doi.org/10.18632/oncotarget.22937

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Abstract

Jie Gao1, Gao-Ju Wang1, Zhao Wang1, Na Gao1, Jing Li1, Yun-Fei Zhang1,2, Jun Zhou1,3, Hong-Xin Zhang1, Qiang Wen1, Han Jin1 and Hai-Ling Qiao1

1 Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China

2 Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China

3 Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China

Correspondence to:

Hai-Ling Qiao, email:

Keywords: cytochrome P450 2E1; hepatic fibrosis; causal role; prevention; diethylnitrosamine; Gerotarget

Received: July 06, 2017 Accepted: November 14, 2017 Published: December 05, 2017

Abstract

Hepatofibrosis, which leads to cirrhosis and eventual hepatocellular carcinoma, is a common response to chronic toxin-mediated liver injury. Nitrosamines are potent hepatotoxic agents that cause necrosis and subsequent fibrosis in the liver as a result of cytochrome P450 2E1 (CYP2E1)-dependent metabolism, which generates toxic metabolites that form adducts with nucleic acids, leading to hepatotoxicity and mutagenesis. Herein, CYP2E1 activity and content were determined in fibrotic liver tissue from patients with hepatocellular carcinoma. The relationship between CYP2E1 innate activity and hepatofibrogenesis was evaluated, the effect of inhibition of CYP2E1 activity on hepatofibrosis was determined in a Sprague-Dawley rat model of diethylnitrosamine-induced hepatofibrosis. The results demonstrated that the CYP2E1 activities in human fibrotic tissues are significantly higher than that in normal liver tissues. In rats treated with diethylnitrosamine, the livers demonstrated various degree of fibrotic changes and collagen deposition in individual rats. The Ishak score, which determines the stage of fibrosis, correlated with CYP2E1 innate activity, with greater fibrosis in rat livers with higher CYP2E1 innate activity. Inhibition of CYP2E1 during diethylnitrosamine treatment decreased hepatofibrosis and there was an inverse correlation between the degree of inhibition and the extent of hepatofibrosis. Therefore, high CYP2E1 activity is a risk factor for hepatofibrogenesis induced by nitrosamines.


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