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Published on: January 19, 2019
Suppression of pulmonary CYP2A13 expression by carcinogen-induced lung tumorigenesis in a CYP2A13-humanized mouse
Zhihua Liu1, Vandana Megaraj1, Lei Li1
1Wadsworth 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.).
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.
Insights
Lung tumors significantly reduce CYP2A13 enzyme levels in mice, suggesting inflammation associated with disease may lower this enzyme
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Cytochrome P450 (P450) enzyme CYP2A13 is crucial for activating tobacco-specific lung carcinogen NNK.
- CYP2A13 expression varies in human lung biopsies, potentially due to inflammation.
- The impact of lung tumors on CYP2A13 expression remains unclear.
Purpose of the Study:
- To investigate if lung tumors suppress CYP2A13 expression in CYP2A13-humanized mice.
- To explore the role of inflammation in regulating CYP2A13 levels in the presence of lung tumors.
Main Methods:
- CYP2A13-humanized mice were treated with NNK to induce lung tumors or saline as a control.
- Lung tissues were analyzed for CYP2A13 protein and mRNA levels.
- Expression of mouse CYP2B10, CYP2F2, and inflammatory cytokines (TNF-α, IFN-γ, IL-6) was measured.
Main Results:
- NNK treatment led to a high incidence of lung tumors.
- Tumor-bearing mice showed significantly reduced CYP2A13 protein and mRNA levels (≥50%) in adjacent normal lung tissue compared to controls.
- Pro-inflammatory cytokine levels were elevated in tumor-bearing mice, indicating inflammation.
Conclusions:
- Lung tumors significantly suppress CYP2A13 expression in mice.
- Disease-associated inflammation likely contributes to the suppression of CYP2A13.
- Findings support the hypothesis that inflammation can lead to underestimation of CYP2A13 levels in human lung tissues.
