1. Glutathione Transferase π Plays a Critical Role in the Development of Lung Carcinogenesis following Exposure to Tobacco-Related Carcinogens and Urethane
- Author
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Kevin Park, Kenneth J. Ritchie, Colin J. Henderson, Olga Vassieva, Xiu Jun Wang, Peter B. Farmer, Margaret Gaskell, C. Roland Wolf, and Dianne Carrie
- Subjects
Adenoma ,Male ,Cancer Research ,Lung Neoplasms ,MAP Kinase Kinase 4 ,7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide ,medicine.disease_cause ,Urethane ,Tobacco smoke ,DNA Adducts ,GSTP1 ,chemistry.chemical_compound ,Tobacco ,Gene expression ,Benzo(a)pyrene ,medicine ,Animals ,RNA, Messenger ,Lung cancer ,Lung ,Carcinogen ,Gene Expression Profiling ,medicine.disease ,Glutathione S-Transferase pi ,Oncology ,Biochemistry ,chemistry ,Toxicity ,Carcinogens ,Cancer research ,Female ,Carcinogenesis - Abstract
Human cancer is controlled by a complex interaction between genetic and environmental factors. Such environmental factors are well defined for smoking-induced lung cancer; however, the roles of specific genes have still to be elucidated. Glutathione transferase π (GSTP) catalyzes the detoxification of electrophilic diol epoxides produced by the metabolism of polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP), a common constituent of tobacco smoke. Activity-altering polymorphisms in Gstp have therefore been speculated to be potential risk modifiers in lung cancer development. To clearly establish a role for GSTP in lung tumorigenesis, we investigated whether deletion of the murine Gstp genes (Gstp1 and Gstp2) alters susceptibility to chemically induced lung tumors following exposure to BaP, 3-methylcholanthrene (3-MC), and urethane. Gstp-null mice were found to have substantially increased numbers of adenomas relative to wild-type mice following exposure to all three compounds (8.3-, 4.3-, and 8.7-fold increase for BaP, 3-MC, and urethane, respectively). In Gstp-null mice, the capacity of pulmonary cytosol to catalyze conjugation of the BaP diol epoxide was significantly reduced. Concomitant with this, a significant increase in the level of BaP DNA adducts was measured in the lungs of null animals; however, no increase in DNA adducts was measured in the case of 3-MC exposure, suggesting that an alternative protective pathway exists. Indeed, significant differences in pulmonary gene expression profiles were also noted between wild-type and null mice. This is the first report to establish a clear correlation between Gstp status and lung cancer in vivo. [Cancer Res 2007;67(19):9248–57] more...
- Published
- 2007
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