title: Suppression of pulmonary CYP2A13 expression by carcinogen-induced lung tumorigenesis in a CYP2A13-humanized mouse model.
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.
authors.affiliation: 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.).
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 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.).
authors.forename: Vandana
authors.initials: V
authors.lastname: Megaraj
authors.affiliation: 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.).
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Stewart
authors.initials: S
authors.lastname: Sell
authors.affiliation: 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.).
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: 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.) xding@sunycnse.com.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D005260:Female; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002273:Carcinogens; D015850:Interleukin-6; D009602:Nitrosamines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D007371:Interferon-gamma; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C110333:Cyp2f2 protein, mouse; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2