The effect of hOGG1 and glutathione peroxidase I genotypes and 3p chromosomal loss on 8-hydroxydeoxyguanosine levels in lung cancer

• Published in: Carcinogenesis (New York) Vol. 21; no. 2; pp. 167 - 172
• Main Authors: Hardie, L.J., Briggs, J.A., Davidson, L.A., Allan, J.M., King, R.F.G.J., Williams, G.I., Wild, C.P.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2000; Oxford Publishing Limited (England)
• Subjects: 2′-deoxyguanosine; 8-hydroxydeoxyguanosine; 8-OHdG; 8-OHdG gene; Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Amino Acid Substitution; apurinic; apurinic lyase; Biological and medical sciences; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; chromosome 3; Chromosomes, Human, Pair 3 - genetics; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - analysis; DNA Adducts; DNA glycosylase; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; DNA-Formamidopyrimidine Glycosylase; Epidemiology; Female; Genotype; glutathione; Glutathione Peroxidase - genetics; Glutathione Peroxidase - physiology; glutathione peroxidase I; GPX1; GPX1 gene; GSH; high pressure liquid chromatography with electrochemical detection; hOGG1 gene; HPLC-ECD; Humans; Isoenzymes - genetics; Isoenzymes - physiology; LOH; Loss of Heterozygosity; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Medical sciences; N-Glycosyl Hydrolases - genetics; N-Glycosyl Hydrolases - physiology; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Oxidative Stress; Polymorphism, Genetic; reactive oxygen species; restriction fragment length polymorphism; RFLP; ROS; Smoking - adverse effects; Tumors; Glutathione peroxidase; Human; Lung disease; Respiratory disease; Enzyme; Genotype; Malignant tumor; Antioxidant; Chromosome 3; Bronchopulmonary; Peroxidases; Mutagenesis; Smoker; Loss of heterozygosity; Deletion; Molecular epidemiology; Bronchus disease; Genetics; Oxidation; Oxidoreductases; Polymorphism
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/21.2.167

Polymorphic genes for the peroxide scavenger glutathione peroxidase I (GPX1) and 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase/apurinic (AP) lyase (hOGG1) map to loci on chromosome 3p which are subject to frequent loss of heterozygosity (LOH) in lung tumours. Levels of the pro-mutagenic, oxidative DNA lesion 8-OHdG, were measured in 37 paired normal and tumorous lung specimens using HPLC with electrochemical detection. Lung tumours were also analysed for 3p LOH by fluorescent PCR with Genescan analysis. No significant difference was observed between 8-OHdG levels in tumour [7.7 ± 6.7 (mean ± SE) 8-OHdG/106 2′-deoxyguanosine (dG)] and normal (8.1 ± 8.8 8-OHdG/106 dG) lung tissue. Adduct levels in normal lung tissue DNA were not associated with constitutive hOGG1 genotype although there was a trend towards lower 8-OHdG levels in individuals possessing the ALA6 GPX1 polymorphism. Lung tumours exhibiting 3p LOH (40%) contained higher levels of 8-OHdG adducts (10.9 ± 2.6 8-OHdG/106 dG) (P = 0.05) and lower GPX1 enzyme activity [45.5 nmol glutathione (GSH)/min/mg] (P = 0.09) when compared with tumours without LOH at these sites (5.55 ± 0.87 8-OHdG/106 dG and 63.6 nmol GSH/min/mg, respectively). In conclusion, tumours with 3p LOH at loci associated with hOGG1 and GPX1 appear to have compromised oxidative defence mechanisms as measured by reduced GPX1 enzyme activity and elevated 8-OHdG levels and this may affect the prognosis of lung cancer patients.