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Rapid CommunicationShort Communication

Suppression of Pulmonary CYP2A13 Expression by Carcinogen-Induced Lung Tumorigenesis in a CYP2A13-Humanized Mouse Model

Zhihua Liu, Vandana Megaraj, Lei Li, Stewart Sell, Jing Hu and Xinxin Ding
Drug Metabolism and Disposition May 2015, 43 (5) 698-702; DOI: https://doi.org/10.1124/dmd.115.063305
Zhihua Liu
Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Z.L., V.M., S.S., J.H., X.D.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.)
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Vandana Megaraj
Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Z.L., V.M., S.S., J.H., X.D.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.)
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Lei Li
Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Z.L., V.M., S.S., J.H., X.D.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.)
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Stewart Sell
Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Z.L., V.M., S.S., J.H., X.D.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.)
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Jing Hu
Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Z.L., V.M., S.S., J.H., X.D.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.)
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Xinxin Ding
Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Z.L., V.M., S.S., J.H., X.D.); College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.)
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Abstract

CYP2A13 is a human cytochrome P450 (P450) enzyme important in the bioactivation of the tobacco-specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). CYP2A13 expression levels vary dramatically among lung biopsy samples from patients, presumably owing in part to a suppression of CYP2A13 expression by disease-associated inflammation. Here, we determined whether CYP2A13 expression in the lungs of CYP2A13-humanized mice is suppressed by the presence of lung tumors. Tissues from an NNK lung tumor bioassay were examined. CYP2A13-humanized mice (95–100%) had multiple lung tumors at 16 weeks after NNK (30 or 50 mg/kg) treatment; whereas only ∼9% of saline-treated CYP2A13-humanized mice had lung tumor (∼1/lung). Mice with lung tumors, from the NNK-treated groups, were used for dissecting adjacent tumor-free lung tissues; whereas mice without visible lung tumors, from the saline-treated group, were used as controls. Compared with the controls, the levels of CYP2A13 protein and mRNA were both reduced significantly (by ≥50%) in the NNK-treated groups. The levels of mouse CYP2B10 and CYP2F2 mRNAs were also significantly lower in the dissected normal lung tissues from tumor-bearing mice than in lungs from the control mice. Pulmonary tissue levels of three proinflammatory cytokines, tumor necrosis factor alpha, interferon gamma, and interleukin-6, were significantly higher in the tumor-bearing mice than in the controls, indicating occurrence of low-grade lung inflammation at the time of necropsy. Taken together, these findings support the hypothesis that CYP2A13 levels in human lungs can be suppressed by disease-associated inflammation in tissue donors, a scenario causing underestimation of CYP2A13 levels in healthy lungs.

Footnotes

    • Received January 9, 2015.
    • Accepted February 11, 2015.
  • This work was supported in part by the National Institutes of Health [Grant CA092596].

  • dx.doi.org/10.1124/dmd.115.063305.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (5)
Drug Metabolism and Disposition
Vol. 43, Issue 5
1 May 2015
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Rapid CommunicationShort Communication

Suppression of CYP2A13 Expression by Lung Tumorigenesis

Zhihua Liu, Vandana Megaraj, Lei Li, Stewart Sell, Jing Hu and Xinxin Ding
Drug Metabolism and Disposition May 1, 2015, 43 (5) 698-702; DOI: https://doi.org/10.1124/dmd.115.063305

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Rapid CommunicationShort Communication

Suppression of CYP2A13 Expression by Lung Tumorigenesis

Zhihua Liu, Vandana Megaraj, Lei Li, Stewart Sell, Jing Hu and Xinxin Ding
Drug Metabolism and Disposition May 1, 2015, 43 (5) 698-702; DOI: https://doi.org/10.1124/dmd.115.063305
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