Polycyclic aromatic hydrocarbon–DNA adducts in smokers and their relationship to micronutrient levels and the glutathione-S-transferase M1 genotype

Abstract

Sixty-three male cigarette smokers were entered into a cross-sectional study to determine whether inverse associations existed between polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels and intake/serum levels of vitamin A, vitamin C and vitamin E. Associations between PAH-DNA adducts and intakes of carotene, as well as serum levels of beta-carotene, were also determined. Fasting blood samples were collected for assays of PAH-DNA adducts in circulating mononuclear cells, plasma cotinine and serum levels of vitamin A, beta-carotene, vitamin C and vitamin E. Since genetic deficiency in the detoxifying enzyme glutathione S-transferase M1 (GSTM1) has been associated with increased risk of lung cancer, GSTM1 genotype was also determined. Analysis of PAH-DNA adducts by competitive enzyme-linked immunosorbent assay (ELISA) indicated that 70% of the subjects had detectable adducts, with a mean of 4.38 adducts/10(8) nucleotides (range 1.00-24.1/10(8)). Pearson's method was utilized to determine whether any associations existed between the various host variables and PAH-DNA adducts. Previously, no significant associations were found between PAH-DNA adducts and cigarettes smoked/day, pack-years, daily/life-time tar exposures or plasma cotinine levels (Santella et al., Carcinogenesis, 13, 2041-2045, 1992). PAH-DNA adducts were inversely associated with serum cholesterol-adjusted vitamin E levels (r = -0.25, P < or = 0.05) and with smoking-adjusted vitamin C serum levels (r = -0.22, P < or = 0.09). Stratification by GSTM1 genotype indicated that these associations were limited to subjects with the null genotype. The relationship between adducts and serum cholesterol-adjusted vitamin E was significant in those of the null genotype (r = -0.38, P < or = 0.04), but not in those with the gene present (r = -0.12, P = 0.5). Similarly, for smoking-adjusted vitamin C, the relationship with adducts was stronger in subjects with the null genotype (r = -0.35, P < or = 0.06) than in those with GSTM1 present (r = -0.05, P = 0.77). These results are consistent with findings of prior epidemiological studies identifying significant inverse associations between anti-oxidant micronutrient status or GSTM1 genotype and the incidence of lung cancer. Additional studies should be conducted to confirm a possible role for vitamin E in PAH-DNA adduct formation and to explore further the possible roles of vitamin A, beta-carotene and vitamin C in modulating adduct formation and lung cancer risk.

DNA adduct burden and tobacco carcinogenesis

“…DNA adducts were found higher in GSTM1 null subjects in the EPIC -Italy study, and were inversely associated with the consumption of fresh fruit, vegetables, olive oil and antioxidants (Palli et al, 2000). Earlier studies suggested an important role for dietary antioxidants on DNA adduct results in smokers (Grinberg-Funes et al, 1994;Mooney et al, 1997). Given the significant role dietary constituents are now thought to play in lung cancer (Williams and Sandler, 2001) further work in this area is needed.…”

“…Glutathione S-transferases and cytochrome P4501A1 Although early studies suggested a role of GSTM1 deficiency in aromatic-hydrophobic DNA adduct levels (Ryberg et al, 1994;Grinberg-Funes et al, 1994;Shields et al, 1993;Kato et al, 1995) these studies were criticized (Cuzick, 1995) for not defining cigarette smoking exposure adequately and for not having sufficient size to adjust for potential statistical artifacts. Continued work on the GSTs has appeared (Table 1) and more recent studies have included polymorphism of the GSTT1 and GSTP1 genes.…”

Molecular epidemiology of smoking and lung cancer

“…In humans, tobacco smoking leads to increased adduct formation in target tissues such as the lung (Phillips et al, 1988;Schoket et al, 1998;Wiencke et al, 1995) and in surrogate tissues such as the blood (Tang et al, 1995;Vineis et al, 1994;Wiencke et al, 1995). Evidence exists that carcinogen-DNA adduct levels are affected by genetic predispositions (Badawi et al, 1995;Grinberg-Funes et al, 1994;Kato et al, 1995;Pastorelli et al, 1998;Rojas et al, 1998;Ryberg et al, 1997;Stern et al, 1993). Several types of studies indicate that carcinogen-DNA adducts are related to cancer risk.…”

Metabolic and DNA Repair Variations in Susceptibility to Genotoxins

“…Fourteen out of 38 studies on exposure to PAHs reported the influence of GSTM1 null (66,102,114,118,122,123,130,132,133,138,142,151,154,156) and, of the 20 studies also examining the genotypes of phase 1 enzymes activating PAHs (CYP1A1), 9 noted the influence on DNA adduct level of mutant genotype CYP1A1 (greater activity) alone or in combination with GSTM1 null (102,122,127,132,(152)(153)(154)(155)157). In four of eight studies on cigarette smoke exposure, in which NAT2 or NAT1 genotypes were considered, increased adduct levels in subjects with the slow acetylator genotype were reported.…”