N-7-Alkyl-2'-Deoxyguanosine as surrogate biomarkers for N-nitrosamine exposure in human lung.
N-Nitrosamines are a large group of chemical compounds that are carcinogenic in animals, and probably in humans. These compounds form DNA adducts, namely 7-methyl-deoxyguanosine monophosphate (7-methyl-dGp) and 7-ethyl-deoxyguanosine monophosphate (7-ethyl-dGp). In study, we have used a combined two-step HPLC and (32)P-postlabeling assay to measure these adducts in the lung tissues of 88 autopsy donors. The mean levels for 7-methyl-dGp and 7-ethyl-dGp were 2.1 ± 0.9 (range 0.4 - 5.3) and 0.9 ± 0.5 (range = 0.1-3.0) adducts per 10(7) dGp. Normal distributions of adduct levels were found. The mean ratio for 7-methyl-dGp to 7-ethyl-dGp was 2.8 (S.D. = 2.3), and the levels were highly correlated (R=0.22, P=0.048). However, this was mostly attributed to nonsmokers. Examinations of adduct levels by race revealed no association with either of adducts studied (P=0.3 and P=0.7 for 7-methyl-dGp and 7-ethyl-dGp, respectively), serum cotinine (P=0.4) or ethanol (P=0.7). Overall, there was no association with smoking status, although there was a borderline correlation of the 7-ethyl-dGp adducts (P=0.09) among men, and for 7-methyl-2'-deoxyguanosine (P=0.03) among women. Women smokers showed higher 7-ethyl-dGp levels than men (P=0.03), and African American smokers had more 7-methyl-dGp levels that Caucasians (P=0.08). This study demonstrates that 7-ethyl-dGp adducts are lower than 7-methyl-dgP adducts in both smokers and non-smokers, but that they were only correlated in nonsmokers. Thus, there is a wide interindividual variation in adduct levels, likely due to differences in N-nitrosamine metabolism, which widens at higher levels of exposure. The presence of lower 7-ethyl-dGp levels in human tissues is consistent with experimental animal studies, yet ethylating N-nitrosamines are more potent than those that cause methylation. Although this study is limited by a small number of study subjects, the findings of higher adduct levels in women and African-American smokers are consistent with the reported increased risk and/or incidence of lung cancer in these groups.
Ganesan
Natarajan
N
Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC-20057.
Kato
Shunji
S
Bowman
Elise D
ED
Shields
Peter G
PG