title: Oxidative Stress and Genetic Variants of Xenobiotic-Metabolising Enzymes Associated with COPD Development and Severity in Serbian Adults.
abstract: The genetic and non-genetic factors that contribute to the development of chronic obstructive pulmonary disease (COPD) are still poorly understood. We investigated the potential role of genetic variants of xenobiotic-metabolising enzymes (glutathione-S-transferase M1, GSTM1; glutathione-S-transferase T1, GSTT1; microsomal epoxide hydrolase, mEH), oxidative stress (assessed by urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxodG/creatinine), sex, ageing and smoking habits on susceptibility to development of COPD and its severity in Serbian population. The investigated population consisted of 153 healthy subjects (85 males and 68 females) and 71 patients with COPD (33 males and 38 females). Detection of GSTM1*null, GSTT1*null, mEH Tyr113His and mEH His139Arg gene variants was performed by PCR/RFLP method. Urinary 8-oxodG was determined using HPLC-MS/MS, and expressed as 8-oxodG/creatinine. We revealed that increased urinary 8-oxodG/creatinine and leucocytosis are the strongest independent predictors for COPD development. Increased level of oxidative stress increased the risk for COPD in males [odds ratio (OR), 95% confidence interval (CI): 8.42, 2.26-31.28], more than in females (OR, 95% CI: 3.60, 1.37-9.45). Additionally, independent predictors for COPD were ageing in males (OR, 95% CI: 1.29, 1.12-1.48), while in females they were at least one GSTM1 or GSTT1 gene deletion in combination (OR, 95% CI: 23.67, 2.62-213.46), and increased cumulative cigarette consumption (OR, 95% CI: 1.09, 1.01-1.16). Severity of COPD was associated with the combined effect of low mEH activity phenotype, high level of oxidative stress and heavy smoking. In conclusion, early identification of GSTM1*null or GSTT1*null genotypes in females, low mEH activity phenotype in heavy smokers and monitoring of oxidative stress level can be useful diagnostic and prognostic biomarkers.
authors.affiliation: a Faculty of Pharmacy, University of Bijeljina , Bijeljina , Bosnia and Herzegovina.
authors.forename: Zivka
authors.initials: Z
authors.lastname: Malic
authors.affiliation: b Department of Medical Biochemistry , Faculty of Pharmacy, University of Belgrade , Belgrade , Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Topic
authors.affiliation: c Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Belgrade , Serbia.
authors.forename: Djordje
authors.initials: D
authors.lastname: Francuski
authors.affiliation: c Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Belgrade , Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Stankovic
authors.affiliation: d Clinic for Pulmonary Diseases Clinical Centre of Serbia, University of Belgrade, School of Medicine , Belgrade , Serbia.
authors.forename: Ljudmila
authors.initials: L
authors.lastname: Nagorni-Obradovic
authors.affiliation: e Department of Pharmaceutical Chemistry , Faculty of Pharmacy, University of Belgrade , Belgrade , Serbia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Markovic
authors.affiliation: c Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Belgrade , Serbia.
authors.forename: Dragica
authors.initials: D
authors.lastname: Radojkovic
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D015415:Biomarkers / Q000652:urine; D015992:Body Mass Index; D016022:Case-Control Studies; D003404:Creatinine / Q000652:urine; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000652:urine; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000652:urine; D012307:Risk Factors; D017384:Sequence Deletion; D055771:Serbia; D012720:Severity of Illness Index; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects / Q000652:urine
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D015415:Biomarkers; D003404:Creatinine; D003849:Deoxyguanosine; D004851:Epoxide Hydrolases; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1
keywords: 8-oxodG/creatinine; COPD; glutathione-S-transferase M1; glutathione-S-transferase T1; microsomal epoxide hydrolase