PT  - JOURNAL ARTICLE
AU  - Zhihua Liu
AU  - Vandana Megaraj
AU  - Lei Li
AU  - Stewart Sell
AU  - Jing Hu
AU  - Xinxin Ding
TI  - Suppression of Pulmonary CYP2A13 Expression by Carcinogen-Induced Lung Tumorigenesis in a CYP2A13-Humanized Mouse Model
AID  - 10.1124/dmd.115.063305
DP  - 2015 May 01
TA  - Drug Metabolism and Disposition
PG  - 698--702
VI  - 43
IP  - 5
4099  - http://dmd.aspetjournals.org/content/43/5/698.short
4100  - http://dmd.aspetjournals.org/content/43/5/698.full
SO  - Drug Metab Dispos2015 May 01; 43
AB  - 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.