Analysis of DNA adducts in smokers' lung and urothelium by 32P-postlabelling: metabolic phenotype dependence and comparisons with other exposure markers.
Carcinogen-DNA adduct levels in lung parenchyma (surgical specimens) and urothelial (exfoliated) cells of smokers, ex-smokers and non-smokers were investigated. DNA adducts were analysed by 32P-postlabelling and levels were compared with tissue-specific activity of cytochrome P450-related enzymes, or whenever possible, with metabolic phenotypes and other macromolecular adducts. Lung cancer patients who were recent smokers had significantly induced benzo[a]pyrene (BaP)-3-hydroxylase (AHH) and ethoxycoumarin O-deethylase activities in lung parenchyma compared with smoking non-cancer patients. Pulmonary AHH activity showed a good correlation with the intensity of immunohistochemical staining for P4501A(1). In lung cancer patients from Italy and Finland who were recent smokers, lung AHH activity was positively correlated (r approximately 0.65; p < 0.001) with bulky DNA adduct levels. In some lung DNA samples from smokers, the level of BaP-diol-epoxide adducts determined by HPLC with fluorescence detection showed significant positive correlation with lung AHH activity and bulky DNA adduct levels. Molecular dosimetry studies provided evidence that aromatic amines such as 4-aminobiphenyl (ABP) in tobacco smoke are primarily responsible for bladder cancer in smokers. The N-(deoxyguanosin-8-yl)-4-ABP adduct was the major smoking-related adduct in DNA of bladder biopsies from bladder cancer patients and in the DNA of exfoliated urothelial cells of smoking volunteers. The adduct levels of ABP with haemoglobin and with deoxyguanosine in urothelial DNA (determined by 32P-postlabelling) were linearly and significantly correlated, and both were related to recent cigarette smoking. Metabolic phenotype (fast/slow N-acetylator and N-oxidizer) significantly affected the levels of ABP-haemoglobin adducts.
Bartsch
H
H
International Agency for Research on Cancer, Lyon, France.
Castegnaro
M
M
Camus
A M
AM
Schouft
A
A
Geneste
O
O
Rojas
M
M
Alexandrov
K
K
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D015415:Biomarkers; D002273:Carcinogens / Q000032:analysis / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000032:analysis* / Q000187:drug effects; D004249:DNA Damage; D006801:Humans; D008168:Lung / Q000737:chemistry / Q000201:enzymology; D008175:Lung Neoplasms / Q000209:etiology / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010641:Phenotype; D010761:Phosphorus Radioisotopes; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism*; D001743:Urinary Bladder / Q000737:chemistry
D015415:Biomarkers; D002273:Carcinogens; D010761:Phosphorus Radioisotopes; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1