Human lung carcinogen-DNA adduct levels mediated by genetic polymorphisms in vivo.
BACKGROUND
Cancer risk from exposure to tobacco smoke varies widely from person to person, depending in part on the status of particular genes and acquired susceptibilities. Certain genes determine how cells activate and detoxify carcinogens. Activated carcinogen metabolites may bind to DNA and form DNA adducts (e.g., 7-methyl-2'-deoxyguanosine-3'-monophosphate [7-methyl-dGMP] and polycyclic aromatic hydrocarbons-dGMP [PAHs-dGMP]), many of which can induce genetic mutations. Thus, if individuals have an increased capacity to activate carcinogens, they might form more carcinogen-DNA adducts and subsequently have an increased risk of cancer.


OBJECTIVE
Using DNA-adduct detection methods specific for 7-methyl-dGMP and PAH-dGMP, we sought to determine whether an inherited genetic susceptibility to cancer associated with certain carcinogen-metabolizing and detoxifying genes (e.g., cytochrome P450 and glutathione S-transferase) is related to DNA adduct formation in lung tissue.


METHODS
Human lung tissues were collected randomly from 90 autopsy donors who were free of cancer. Levels of 7-methyl-dGMP, a metabolic product of N-nitrosamines, and PAH-dGMP adducts were determined in lung tissue specimens by use of micropreparative DNA purification steps combined with a 32P-postlabeling assay. Genetic polymorphisms (the presence of different genes and/or alleles) were determined for the cytochrome P450 genes, CYP2D6, CYP2E1, and CYP1A1, as well as for glutathione S-transferase M1 (GSTM1). Statistical differences among adduct levels for the study variables, including genotypes, were assessed by the two-sided Student's t test or the Mann-Whitney U test.


RESULTS
Higher 7-methyl-dGMP adduct levels were associated with CYP2D6 genotypes (P = .01), consistent with the reports of the increased risk of lung cancer associated with this genotype. Higher adduct levels were also associated with CYP2E1 minor alleles (P = .05). In both cases, the association was attributed mostly to individuals with low serum cotinine levels (P = .004 and P = .05, respectively), suggesting that the effect of the genotypes is mostly in nonsmokers exposed to either passive tobacco smoke or to N-nitrosamine exposures other than tobacco smoke or to N-nitrosamine exposures other than tobacco smoke. Separately, the presence of PAH-dGMP adducts was associated with the GSTM1 null genotype (absence of the gene) (odds ratio = 8.6; 95% confidence interval = 1.03-100).


CONCLUSIONS
This study finds that the levels of two different carcinogen-DNA adducts vary in lung tissue (an important target tissue) in association with three separate genetic polymorphisms (i.e., CYP2D6, CYP2E1, and GSTM1). CYP2D6 and CYP2E1 genotypes are associated with higher 7-methyl-dGMP levels, while the GSTM1 null genotype is associated with higher numbers of PAH-dGMP adducts. These findings suggest that genetic polymorphisms are predictive of carcinogen-DNA adduct levels and would thus be predictive of an individual's lifetime response to carcinogen exposure.
Kato
S
S
Division of Cancer Etiology, National Cancer Institute, Bethesda, Md 20892, USA.
Bowman
E D
ED
Harrington
A M
AM
Blomeke
B
B
Shields
P G
PG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D003367:Cotinine / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003848:Deoxyguanine Nucleotides / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011083:Polycyclic Compounds / Q000378:metabolism*; D011110:Polymorphism, Genetic; D012907:Smoking / Q000097:blood / Q000235:genetics
D003848:Deoxyguanine Nucleotides; D011083:Polycyclic Compounds; C060943:7-methyl-2'-deoxyguanosine 3'-monophosphate; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D003367:Cotinine