Serum paraoxonase and arylesterase activities in patients with lung cancer in a Turkish population

BACKGROUND: Lung cancer (LC) is the leading cause of cancer-related deaths. Oxidative DNA damage may contribute to the cancer risk. The antioxidant paraoxonase (PON1) is an endogenous free radical scavenger in the human body. The aim of this study was to determine serum PON1 and arylesterase (ARE) activities in patients with newly diagnosed LC. METHODS: This case control study involved a total of 39 patients with newly diagnosed LC (untreated) and same number of age- and sex-matched healthy individuals. Serum PON1 and ARE activities in addition to lipid parameters were measured in both groups. RESULTS: Serum PON1 and ARE activities were found to be lower in patients with LC compared to the controls (p = 0.001 and p = 0.018, respectively). The ratio of PON1/high density lipoprotein (HDL) was significantly lower in the LC group compared to the control one (p = 0.009). There were positive correlations between the serum levels of HDL and PON1 in both the control (r = 0.415, p = 0.009) and the LC groups (r = 0.496, p = 0.001), respectively. PON1 enzyme activity was calculated as three different phenotypes in both groups. In regard to lipid parameters, total cholesterol levels were significantly lower (p = 0.014) in the LC group whereas the other lipid parameters such as HDL, LDL, and triglyceride levels were not significantly different among groups. CONCLUSION: Serum PON1 activity is significantly low in the LC group compared with the healthy controls. Metastasis status and cigarette smoking do not affect serum PON1 activity in the LC patients

Therapeutic Dosing of Acenocoumarol: Proposal of a Population Specific Pharmacogenetic Dosing Algorithm and Its Validation in North Indians

Objectives: To develop a population specific pharmacogenetic acenocoumarol dosing algorithm for north Indian patients and show its efficiency in dosage prediction. Methods: Multiple and linear stepwise regression analyses were used to include age, sex, height, weight, body surface area, smoking status, VKORC1-1639 G.A, CYP4F2 1347 G.A, CYP2C9*2,*3 and GGCX 12970 C.G polymorphisms as variables to generate dosing algorithms. The new dosing models were compared with already reported algorithms and also with the clinical data for various performance measures. Odds ratios for association of genotypes with drug sensitive and resistant groups were calculated. Results: The pharmacogenetic dosing algorithm generated by multiple regression analysis explains 41.4 % (p-value,0.001) of dosage variation. Validation of the new algorithm showed its predictive ability to be better than the already established algorithms based on similar variables. Its validity in our population is reflected by increased sensitivity, specificity, accuracy and decreased rates of over- and under- estimation in comparison to clinical data. The VKORC1-1639 G.A polymorphism was found to be strongly associated with acenocoumarol sensitivity according to recessive model. Conclusions: We have proposed an efficient north India specific pharmacogenetic acenocoumarol dosing algorithm whic

Glutathione S-transferase genotypes modify lung function decline in the general population: SAPALDIA cohort study

BACKGROUND: Understanding the environmental and genetic risk factors of accelerated lung function decline in the general population is a first step in a prevention strategy against the worldwide increasing respiratory pathology of chronic obstructive pulmonary disease (COPD). Deficiency in antioxidative and detoxifying Glutathione S-transferase (GST) gene has been associated with poorer lung function in children, smokers and patients with respiratory diseases. In the present study, we assessed whether low activity variants in GST genes are also associated with accelerated lung function decline in the general adult population. METHODS: We examined with multiple regression analysis the association of polymorphisms in GSTM1, GSTT1 and GSTP1 genes with annual decline in FEV1, FVC, and FEF(25–75 )during 11 years of follow-up in 4686 subjects of the prospective SAPALDIA cohort representative of the Swiss general population. Effect modification by smoking, gender, bronchial hyperresponisveness and age was studied. RESULTS: The associations of GST genotypes with FEV1, FVC, and FEF(25–75 )were comparable in direction, but most consistent for FEV1. GSTT1 homozygous gene deletion alone or in combination with GSTM1 homozygous gene deletion was associated with excess decline in FEV1 in men, but not women, irrespective of smoking status. The additional mean annual decline in FEV1 in men with GSTT1 and concurrent GSTM1 gene deletion was -8.3 ml/yr (95% confidence interval: -12.6 to -3.9) relative to men without these gene deletions. The GSTT1 effect on the FEV1 decline comparable to the observed difference in FEV1 decline between never and persistent smoking men. Effect modification by gender was statistically significant. CONCLUSION: Our results suggest that genetic GSTT1 deficiency is a prevalent and strong determinant of accelerated lung function decline in the male general population

genotype in patients with bronchial asthma

Background GlutathioneS-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferases (GSTs) in lung epithelium, plays an important role in cellular protection against oxidative stress and toxic foreign chemicals. It has been suggested that polymorphisms in the GSTP1 gene are associated with asthma and related phenotypes. As significant interindividual and interethnic differences exist in the distribution of xenobiotic-metabolizing enzymes, we have studied the GSTP1 Ile105Val polymorphism in patients with asthma in a Turkish sample.Methods GSTP1 Ile105Val polymorphism in exon 5 was determined in 210 patients with asthma (112 extrinsic and 108 intrinsic) and 265 control individuals without lung diseases and without history of allergy or atopy, using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) techniques.Results The proportion of GSTP1 Val105 homozygotes was significantly lower in the patients with asthma than in the control individuals (3.8% vs 12.1%). The odds ratio for GSTP1 Val105 homozygotes vs all other genotypes was 0.29 (95% CL 0.13-0.64, p = 0.01) for asthmatics. The distribution of GSTP1 Ile105Val genotypes and the frequency of GSTP1 Val105Val homozygotes (3.7% vs 3.9%) was not significantly different between extrinsic and intrinsic asthmatics.Conclusions These results suggest a significant association between GSTP1 Ile105Val polymorphism and susceptibility to asthma and that the GSTP1 Val105Val genotype may be protective against developing this disease

Protective role of glutathione S-transferase P1 (GSTP1) Val105Val genotype in patients with bronchial asthma.

BACKGROUND: Glutathione S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferases (GSTs) in lung epithelium, plays an important role in cellular protection against oxidative stress and toxic foreign chemicals. It has been suggested that polymorphisms in the GSTP1 gene are associated with asthma and related phenotypes. As significant interindividual and interethnic differences exist in the distribution of xenobiotic-metabolizing enzymes, we have studied the GSTP1 Ile105Val polymorphism in patients with asthma in a Turkish sample. METHODS: GSTP1 Ile105Val polymorphism in exon 5 was determined in 210 patients with asthma (112 extrinsic and 108 intrinsic) and 265 control individuals without lung diseases and without history of allergy or atopy, using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) techniques. RESULTS: The proportion of GSTP1 Val105 homozygotes was significantly lower in the patients with asthma than in the control individuals (3.8% vs 12.1%). The odds ratio for GSTP1 Val105 homozygotes vs all other genotypes was 0.29 (95%CL 0.13-0.64, p = 0.01) for asthmatics. The distribution of GSTP1 Ile105Val genotypes and the frequency of GSTP1 Val105Val homozygotes (3.7% vs 3.9%) was not significantly different between extrinsic and intrinsic asthmatics. CONCLUSION: These results suggest a significant association between GSTP1 Ile105Val polymorphism and susceptibility to asthma and that the GSTP1 Val105Val genotype may be protective against developing this disease

N-acetyltransferase polymorphism in patients with Behcet's disease

Objectives: The objective of our study was to investigate the possible role of human arylamine N-acetyltransferase 2 (NAT2) polymorphism in susceptibility to Behcet's disease.Methods: Eighty-five patients with Behcet's disease gave their written informed consent to participate in the study. Seven point mutations (G191A, C282T, T341C, C481T, A803G, G590A, G857A) in the NAT2 gene were analysed using polymerase chain reaction/restriction fragment length polymorphism techniques. In addition, each patient received 100 mg dapsone orally to determine their NAT2 phenotype. Dapsone and its metabolite monoacetyl-dapsone were measured in 3-h plasma samples using high-performance liquid chromatography. Subjects with an acetylation ratio (monoacetyl-dapsone/dapsone) less than 0.4 were defined as slow acetylators.Results: Of 85 patients with Behcet's disease, 54 (63.5%) were identified as genotypically slow acetylators. However, 60% (51 of 85) of patients were diagnosed as slow acetylators according to mono acetyl-dapsone/dapsone ratio. Thus, a low incidence of genotype/phenotype discrepancy (3.5%) was observed in Turkish patients with Behcet's disease. When we compared our results with previous phenotyping and genotyping studies in the Turkish population, frequencies of slow and rapid acetylators were not statistically different in patients with Behcet's disease. The frequency of the *5B allele was found to be slightly higher in patients with Behcet's disease than historic controls (44.7 vs 35.6%, P=0.039). However, there was no significant difference in the frequency of the overall genotypes and alleles of NAT2 between patients and controls.Conclusion: Although the frequency of the NAT2*5B allele, responsible for slow acetylation, was slightly higher in patients than historic controls, our results failed to show an association between NAT2-acetylator status and risk for developing Behget's disease