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Research ArticleMetabolism, Transport, and Pharmacogenomics

Higher CYP2E1 Activity Correlates with Hepatocarcinogenesis Induced by Diethylnitrosamine

Jie Gao, Zhao Wang, Gao-Ju Wang, Hong-Xin Zhang, Na Gao, Jie Wang, Cai-E. Wang, Zhao Chang, Yan Fang, Yun-Fei Zhang, Jun Zhou, Han Jin and Hai-Ling Qiao
Journal of Pharmacology and Experimental Therapeutics May 2018, 365 (2) 398-407; DOI: https://doi.org/10.1124/jpet.117.245555
Jie Gao
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Zhao Wang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Gao-Ju Wang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Hong-Xin Zhang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Na Gao
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Jie Wang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Cai-E. Wang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Zhao Chang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Yan Fang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Yun-Fei Zhang
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Jun Zhou
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Han Jin
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Hai-Ling Qiao
Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China (J.G., Z.W., G.-J.W., H.-X.Z., N.G., J.W., C.-E.W., Z.C., Y.F., Y.-F.Z., J.Z., H.J., H.-L.Q.); First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (H.-X.Z.); Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China (Y.-F.Z.); and Affiliated Provincial People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China (J.Z.)
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Abstract

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.

Footnotes

    • Received October 6, 2017.
    • Accepted January 8, 2018.
  • ↵1 J.G., Z.W., and G.-J.W. contributed equally to this work.

  • This work was supported by the National Natural Science Foundation of China (Nos. 81473279 and 81673507 to H.-L.Q).

  • https://doi.org/10.1124/jpet.117.245555.

  • Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 365 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 365, Issue 2
1 May 2018
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Research ArticleMetabolism, Transport, and Pharmacogenomics

CYP2E1 Activity and Hepatocarcinogenesis

Jie Gao, Zhao Wang, Gao-Ju Wang, Hong-Xin Zhang, Na Gao, Jie Wang, Cai-E. Wang, Zhao Chang, Yan Fang, Yun-Fei Zhang, Jun Zhou, Han Jin and Hai-Ling Qiao
Journal of Pharmacology and Experimental Therapeutics May 1, 2018, 365 (2) 398-407; DOI: https://doi.org/10.1124/jpet.117.245555

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Research ArticleMetabolism, Transport, and Pharmacogenomics

CYP2E1 Activity and Hepatocarcinogenesis

Jie Gao, Zhao Wang, Gao-Ju Wang, Hong-Xin Zhang, Na Gao, Jie Wang, Cai-E. Wang, Zhao Chang, Yan Fang, Yun-Fei Zhang, Jun Zhou, Han Jin and Hai-Ling Qiao
Journal of Pharmacology and Experimental Therapeutics May 1, 2018, 365 (2) 398-407; DOI: https://doi.org/10.1124/jpet.117.245555
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