Expression of pulmonary cytochrome P4501A1 and carcinogen DNA adduct formation in high risk subjects for tobacco-related lung cancer.
Cigarette smoking is the strongest risk factor for lung cancer (LC), but genetically determined variations in pulmonary metabolism of tobacco-derived carcinogens may affect individual risk. Results from a case-control study on LC patients demonstrated the pronounced effect of tobacco smoke on pulmonary xenobiotic metabolism and prooxidant state, and suggested the existence of a metabolic phenotype at higher risk for tobacco-associated LC: LC patients who were recent smokers had significantly induced BP-3-hydroxylase (AHH) and ethoxycoumarin O-deethylase (ECDE) activities in lung parenchyma, when compared with smoking non-cancer patients. In recent smokers, lung AHH activity was positively correlated with the level of tobacco smoke-derived DNA adducts as determined by 32P-postlabelling. Pulmonary AHH activity also showed a good correlation with the intensity of immunohistochemical staining for cyt. P4501A by a monoclonal Ab in lung tissue sections: smoking and peripheral type of lung cancers were positively related to high levels of this cyt. P450 species, probably reflecting high rates of induction. These results suggest that high pulmonary CYP1A1 expression (controlling in part carcinogen DNA-adduct formation) in tobacco smokers, appears to be associated with LC risk. High risk subjects may thus be identifiable through genotyping assays for CYP1A1 polymorphism.
Bartsch
H
H
International Agency for Research on Cancer, Lyon, France.
Castegnaro
M
M
Rojas
M
M
Camus
A M
AM
Alexandrov
K
K
Lang
M
M
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004790:Enzyme Induction; D006801:Humans; D008168:Lung / Q000201:enzymology*; D008175:Lung Neoplasms / Q000209:etiology*; D012306:Risk; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism
D002273:Carcinogens; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases