Investigation of epoxide hydrolase, glutathione-s-transferase, cytochrome p450 1a1 gene polymorphisms in relation to respiratory disorders induced by environmental pollutants

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is characterized by irreversible airflow limitation, abnormal permanent distal air-space enlargement and emphysema in the lungs. Complex interactions between genetic factors and the environment have been suggested predisposition to the disorder. Moreover, the fact that only few individuals out of those exposed to similar conditions develop COPD points to differences in the genetic constitution. Xenobiotic metabolism and oxidative stress are of importance, whose imbalance due to risk factor exposure has the potential to cause COPD and the variations in the genes could be one of the major causative factors. In the present thesis, the polymorphism approach is used to investigate the possible associations of the candidate genes of xenobiotic metabolizing and oxidative stress viz. microsomal Epoxide Hydrolase (mEPHX), Glutathione-S-Transferase P1 (GSTP1), Cytochrome P450 1A1, 1A2 (CYP1A1, CYP1A2) and NADPH oxidase p22phox (CYBA), with COPD. Estimations of plasma malondialdehyde (MDA), reduced glutathione (GSH) levels, Catalase (CAT) and glutathione peroxidase (GPx) activities were measured out to look for a genotype-phenotype correlation. The studies on mice model exposed to acute cigarette smoke revealed the molecular complexity of disease pathogenesis at biochemical and molecular levels. The literature pertinent to the objectives of the present thesis is provided in Chapter 1. The objectives of the present thesis were the following The objectives of Chapter 2 was to examine the imbalance in the oxidative status and to ascertain if a relationship existed between oxidative status, BMI and lung function in COPD. Plasma LPO, GSH level, GPx, CAT activities, BMI and FEV1 % predicted were looked for interactions. The study pointed that the COPD patients have impaired status of oxidant-antioxidants balance and the intimate relationship of oxidant-antioxidants with BMI and lung function may potentiates severity of the disease. Even in pathophysiology, the direct correlation between BMI and FEV1 % predicted may be important. The genetic susceptibility to COPD might depend on variations in detoxification genes that activate and detoxify cigarette smoke products and oxidative stress genes.