Abstract B91: Functional polymorphisms in endogenous antioxidant defense genes and oxidative stress levels in women: A genotype-phenotype study

Abstract

Abstract Superoxide dismutase, glutathione peroxidase, and catalase are the primary endogenous antioxidant defense enzymes that provide protection against reactive oxygen species — molecules that are known to cause damage to DNA, lipids, and proteins. The genes that encode these antioxidant enzymes are polymorphic, and three common single nucleotide polymorphisms — MnSOD Val16Ala, GPX1 Pro198 Leu, and CAT −262 C>T -yield enzymes that display altered activity. These variants have been linked with risks of cancer at multiple sites, either directly or indirectly through interactions with dietary intakes of antioxidant nutrients or antioxidant-rich foods. Although it is generally presumed that these polymorphisms influence cancer risk by altering the host's ability to combat toxic free radicals, very few studies have directly tested this hypothesis in non-diseased individuals. We therefore evaluated whether urinary concentrations of 8-isoprostane F2 (8-iso-PGF2α) — the most sensitive indicator of lipid peroxidation, a biomarker for oxidative stress — vary across the aforementioned antioxidant defense genotypes in 87 young, healthy women randomized to the control arm of the Diet and Hormone Study — a low fat, high fruit and vegetable dietary intervention trial. 8-iso-PGF2α was measured in pre-randomization 24-hour urine samples by liquid chromatography- tandem mass spectrometry, and genotypes were determined in DNA extracted from buffy coat using the Taqman assay. 8-iso-PGF2α concentrations were significantly higher in overweight women, in those who were less well educated, and among participants with low serum β-carotene levels or high dietary intakes of γ-tocopherol or iron. Lipid peroxidation levels did not vary with age, race, smoking status, alcohol consumption, physical activity, fruit and vegetable intake, or vitamin supplement use. In multiple linear regression models, there was no evidence of a trend in urinary 8-iso-PGF2α concentrations across the MnSOD Val16Ala or GPX1 Pro198 Leu genotypes (for MnSOD val/val, ala/val, and ala/ala genotypes, mean 8-iso-PGF2α = 173, 213, and 193 pg/mL, respectively, p-trend = 0.63; for GPX1 Pro/Pro, Leu/Pro, and Leu/Leu genotypes, mean 8-iso-PGF2α = 185, 263, and 190 pg/mL, respectively, p-trend = 0.18). Contrary to expectation, urinary 8-iso-PGF2α concentrations decreased across the CAT −262 C>T genotypes such that carriers of the homozygous (less active) TT genotype exhibited the lowest lipid peroxidation levels (for CC, TC, and TT genotypes, mean 8-iso-PGF2α = 232, 179, and 93 pg/mL, respectively, p-trend=0.07). These results indicate that functional polymorphisms in endogenous antioxidant defense genes do not correspond with higher lipid peroxidation levels in young, healthy women. Ongoing analyses will determine whether urinary concentrations of 8-hydroxydeoxguanosine — a biomarker of DNA damage — vary across these antioxidant defense genotypes. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B91.