A cross-sectional study of polycyclic aromatic hydrocarbon-DNA adducts and polymorphism of glutathioneS-transferases among heavy smokers by race/ethnicity

Abstract

Differences in lung cancer risk by race/ethnicity have been observed among smokers. To determine whether these observations might reflect differences in the formation of carcinogen-DNA adducts, we analysed blood specimens (n=151) collected from smokers who were recruited for possible participation in an antioxidant vitamin intervention study. Mononuclear cells were analysed for polycyclic aromatic hydrocarbon (PAH)-DNA adducts by competitive enzyme-linked immunosorbent assay. Genotypes of glutathione S-transferase M1 and P1 (GSTM1 and GSTP1), enzymes involved in the detoxification of PAH metabolites, were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism, respectively. GSTM1 was present in 65 out of 88 (73.4%), 16 out of 32 (50.0%) and 16 out of 29 (54.8%) of African-Americans, Caucasians and Latinos, respectively (p=0.022). Homozygosity for the GSTP1 codon 105 variant was found in 25.6%, 6.3% and 10.0% of African-Americans, Caucasians and Latinos, respectively (p=0.023). Regression analysis of the log-transformed adduct levels confirmed that Caucasian and Latino subjects had lower PAH-DNA adduct levels than African-American subjects, after adjustment for gender, education, alpha-tocopherol and beta-carotene levels, and GSTM1 status. Further adjustment for age and current smoking habits had no impact on these findings. Although crude analysis suggested that the GSTM1-positive genotype may be associated with lower PAH-DNA levels in Caucasians (but not in African-Americans or Latinos), a formal test for interaction between GSTM1 and ethnicity was not significant. We found no association between adduct levels and GSTP1 genotype. Although the mechanism is unclear, ethnic differences in DNA damage levels may in part explain why African-Americans have higher lung cancer incidence rates than other ethnic groups.

Associations between Smoking, Polymorphisms in Polycyclic Aromatic Hydrocarbon (PAH) Metabolism and Conjugation Genes and PAH-DNA Adducts in Prostate Tumors Differ by Race

“…Differences between ethnic groups were not totally unexpected, because African Americans, compared with Caucasians generally present with prostate cancer at an earlier age and with more advanced disease, have higher prostate cancer mortality rates (4) and higher PAH-DNA adduct levels in mononuclear cells (51). Associations between genetic polymorphisms and PAH-DNA adducts may differ by race due to differences in PAH exposure.…”

“…Although associations between a few of the aforementioned polymorphisms in metabolism and conjugation genes and PAH-DNA adduct levels have been examined in human lung (48) and breast (49,50) cancer tissues and differences in PAH-DNA adduct levels by race in mononuclear cells have been reported (51), no prior studies have evaluated effects of these polymorphisms on adduct levels in human prostate cancer tissues. Therefore, in this study, we extend our earlier work …”

Antibodies to Benzo[a]pyrene and Polymorphisms of Cyp1a1*2a, Cyp1a2*1f, Gstt1, and Gstm1 Genes in Healthy Men and Lung Cancer Patients

“…Это свидетельствует об определяющем значении эндогенных факторов в регуляции специфиче-ского иммунного ответа на химические канцеро-гены окружающей среды. Результаты многочисленных исследований полиморфизма генов биотрансформации ксено-биотиков остаются противоречивыми, одним ав-торам удается обнаружить ассоциации с риском РЛ, другие отрицают такие связи [1,2,21,28,37,41,42]. В нашей работе также не выявлены раз-личия между здоровыми донорами и больными РЛ по частоте встречаемости отдельных аллелей и генотипов CYP1A1*2А (rs4646903), CYP1A2*1F…”

“…Считается, что генетический полиморфизм ферментов биотрансформации низкомолеку-лярных ксенобиотиков CYP, GST является одним из эндогенных факторов канцерогенеза [1,2,21,28,30,37,38,41]. Аддукты метаболитов канце-рогенов с ДНК и белками, а также специфичные к ним АТ действительно обнаружены у людей, подвергающихся интенсивному канцерогенному воздействию [4,5,7,9,17,20,22,23,26,27,31,32,42,43]. А у больных злокачественными опухо-лями выявлено большее количество АТ к хими-ческим канцерогенам, чем у здоровых [3,12,39].…”

Residential Segregation, Housing Status, and Prostate Cancer in African American and White Men

“…In a similar manner, high PAH-DNA adduct levels may better discriminate between aggressive and nonaggressive prostate cancer phenotypes in younger versus older cases. Few studies have examined racial differences in PAH-DNA adduct levels, but a study of smokers found that African American subjects had higher adduct levels in lymphocytes than Caucasian and Latino subjects after adjustment for gender, education, a-tocopherol and h-carotene levels, and GSTM1 status (55).…”