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Suppression of Pulmonary CYP2A13 Expression by Carcinogen‐Induced Lung Tumorigenesis in a CYP2A13‐Humanized Mouse Model
Author(s) -
Ding Xinxin,
Liu Zhihua,
Megaraj Vandana,
Li Lei,
Sells Stewart,
Hu Jin
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.778.10
Subject(s) - lung , carcinogen , carcinogenesis , humanized mouse , saline , pathology , respiratory tract , medicine , lung cancer , immunology , respiratory system , biology , cancer , immune system , genetics
CYP2A13, a human P450 enzyme preferentially expressed in the respiratory tract, is important in the bioactivation of many environmental carcinogens, including tobacco‐specific nitrosamines. The aim of this study is to determine whether lung tumorigenesis causes decreases in CYP2A13 expression in the lungs of a CYP2A13‐humanized mouse model. Tissues from a NNK lung tumor bioassay for female CYP2A13‐humanized mice were examined. NNK‐treated CYP2A13‐humanized mice had observable lung tumors at 16 weeks after the NNK treatment (tumor frequency: 100% and 95%; tumor multiplicity: 13.1 and 4.4 tumors per lung; for the 50‐ and 30‐mg/kg NNK dose groups, respectively); whereas only ~9% of saline‐treated CYP2A13‐humanized mice had lung tumor (~1/lung). Ten mice with lung tumors, from each of the two NNK‐treated groups, were used for dissecting adjacent tumor‐free lung tissues; whereas three mice without visible lung tumors, from the saline‐treated group, were used as controls. Compared to the saline treated group, the level of CYP2A13 protein was reduced significantly (by >50%) in both NNK‐treated groups; CYP2A13 mRNA levels were also decreased, by ~50% in the 30 mg/kg group and ~80% in the 50 mg/kg group. 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 saline treated control mice. These findings support the hypothesis that CYP2A13 levels in human lung can be suppressed by inflammation associated with disease status in tissue donors, causing underestimation of CYP2A13 levels in healthy lungs.