Yavuz Silig

Carnitine Deficiency in Diabetes Mellitus Complications

In this study, the serum total, free and ester carnitine levels in 24 type II diabetes mellitus (DM) patients with complications and 15 type II DM patients with no complications were investigated. The patients were investigated in four groups; the control group included the patients with no complications (group 1), the groups including the patients with retinopathy (group 2), hyperlipidemia (group 3), and neuropathy (group 4). In addition, patients were grouped into two. The first group included 10 patients who took insulin by injection (group 5), and the second group included 29 patients using antidiabetic drugs orally (OAD) (group 6). Free and ester carnitine levels were determined by using Boehringer Manheim UV-enzymatic L-carnitine kit. Statistical analysis results showed that both the plasma total and free carnitine levels of groups 2, 3, and 4 were found to be low when compared to the levels of group 1 (p < 0.05). It was observed that the plasma total and free carnitine levels of group 5 were lower when compared to group 6. No significant difference was observed between the plasma ester carnitine levels of all the groups investigated. As a result of this study, it has been thought that carnitine plays an important role in diabetes mellitus complications.

Strong association between the GSTM1-null genotype and lung cancer in a Turkish population

Glutathione S-transferases are possibly related to the detoxification of many xenobiotics involved in the etiology of cancer. To investigate the role of the glutathione S-transferase M1 deletion (GSTM1-null) in lung cancer, the polymerase chain reaction was used to determine the GSTM1 genotypes of lung cancer patients (n=101) and hospital (n=206) in a Turkish population. The prevalence of the GSTM1-null genotype in the case group was 48%, compared to 18% in the control group, giving an odds ratio (OR) of 4.14 (95% confidence interval [CI]=2.36-7.27). The analysis of patients by histologic type of lung cancer (10% adenocarcinoma, 43% squamous cell carcinoma, 26% small cell carcinoma, and 11% large cell carcinoma) showed no association between histopathologic type of lung cancer and GSTM1-null genotype. When the interaction between the GSTM1-null genotype and smoking status was analyzed, among the 67 smokers, the GSTM1-null genotype was found in 37 (55%) with an OR of 2.58 (95% CI=1.00-6.73) indicating a significant association. However, no association was found between smoking exposure (<30 and > or =30 packs/year) and GSTM1-null genotype. We conclude that, in this study the null GSTM1 genotype is an independent risk factor for the development of lung cancer for Turkish population.

Polymorphisms of CYP1A1, GSTM1, GSTT1, and Prostate Cancer Risk in Turkish Population

Prostate cancer is the most common cancer among men in many countries. Although the etiology of prostate cancer largely is unknown, both genetic and environmental factors may be involved. Advanced age, androgen metabolism, and heredity-race have been reported to be possible risk factors. On the other hand, several studies indicate that genetic polymorphisms in biotransformation enzymes play a role in prostate cancer development. In this study, association of the prostate cancer risk with genotype frequencies of the Phase I (CYP1A1) and Phase II (GSTM1 and GSTT1) biotransformation enzymes was investigated in 321 Turkish individuals (152 prostate cancer patients and 169 age-matched male controls). The presence or absences of the GSTM1 and GSTT1 genes were determined by a PCR-based method. Genotypes of CYP1A1 were determined by MspI-RFLP. The prevalence of GSTM1 null genotype in the cases was 64 percent, compared to 31 percent in the control group, indicating a strong association (OR = 4.08, 95%CI = 2.50–6.69). No association was observed between either GSTT1 null genotype or CYP1A1 polymorphism and prostate cancer incidence. No statistically significant association was observed between smoking status of the patients and any of the polymorphisms studied. In conclusion, results of this study indicate that only the GSTM1 null genotype may play an important role as a risk factor for prostate cancer development in Turkish population.

The Association Between Polymorphisms in Glutathione S-Transferase (GSTM1 and GSTT1) and Lung Cancer Outcome

Background: Polymorphisms in the glutathione S-transferase (GST) family may be associated with increased risk of lung cancer, somatic changes in lung tumour tissue, and survival. We evaluated survival according to GST polymorphism in lung cancer patients. Methods: We studied DNA polymorphisms of 81 primary lung cancer patients at 2 glutathione-related loci: GSTM1, and GSTT1 that encode glutathione S-transferase-μ, and glutathione S-transferase-□. The presences of the GSTM1 and GSTT1 genes were assayed by PCR. Kaplan-Meier with log rank tests, and Cox regression models were applied in the analysis. Results: The median age of 75 males and 6 females was 60 years. Median survival of the whole population was 8 months. In the first presentation, none of the patients with GSTT1 null genotype but 30 percent of the patients with GSTT1-positive genotype had liver metastasis (p < 0.01) but GSTT1 genotype was not associated with survival. Sputum (p < 0.01) was more common in patients with GSTM1 null genotype. Subjects with the GSTM1-null genotype had shorter survival. Using a Cox proportional hazard model, GSTM1, tumor (T) factor and thoracic irradiation status were identified as independent prognostic factors. Conclusions: Our preliminary results showed that GSTM1-null genotype was associated with shorter survival.

Strong association between lung cancer and the AXIN2 polymorphism.

Accumulated evidence suggests that alterations due to mutations or genetic polymorphisms in the AXIN2 tumor suppressor gene, a component of the Wnt signaling pathway, contributes to carcinogenesis. The effect of the AXIN2 exon 1 148 C↷T polymorphism was recently investigated in a Japanese population, but has not been investigated in other populations. Additionally, other common polymorphisms of this gene have not been studied. In the present study, 8 polymorphisms of the AXIN2 gene, including exon 1 148 C↷T, were investigated in a Turkish population of 100 lung cancer patients using PCR-RFLP methods. For the exon 1 432 C↷T, exon 5 1365 G↷A, exon 5 1386 C↷T, intron 5 1712+19 G↷T, exon 7 2062 C↷T and intron 7 2141+73 G↷A single nucleotide polymorphisms of AXIN2, no significant association was found between the controls and the lung cancer patients. For exon 1 148 C↷T, a statistically significant association between the controls and lung cancer patients was found. For this region, lung cancer patients with the TT genotype showed a decreased risk [odds ratio (ORTT) 0.33, 95% confidence interval (CI) 0.12-0.89; p=0.032 (adjusted for age, gender and smoking status)] as compared with the controls with the CC genotype. Concerning histological tumor type, it has been found that exon 1 148 C↷T SNP is associated with a significant decreased risk in squamous cell carcinoma patients (ORTT 0.16; 95% CI 0.03-0.79; p=0.014). Male (ORTT 0.19; 95% CI 0.04-0.77; p=0.015) and smoker (ORTT 0.11; 95% CI 0.01-0.71; p=0.019) lung cancer patients with the TT genotype showed a decreased risk for the same region. Our results suggest that the risk of lung cancer in a Turkish population is related to polymorphisms of the AXIN2 gene.

Myeloperoxidase G-463A polymorphism and risk of lung and prostate cancer in a Turkish population.

Myeloperoxidase (MPO) is a phase I enzyme that can bioactivate many specific procarcinogens, including polycyclic aromatic hydrocarbons and aromatic amines. The MPO gene contains a common single nucleotide polymorphism, for which the -463G>A substitution within the promoter region has been shown to reduce MPO expression and activity. We investigated the association between the MPO -463G>A polymorphism and lung and prostate cancer in a Turkish population. MPO genotypes in the study populations were determined using polymerase chain reaction-based restriction fragment length polymorphism assay. The allelic frequency was significantly different between the cases and controls for lung cancer (p=0.02), but not prostate cancer (p=0.30). No significant difference was noted between the lung and prostate cancer cases and control populations in terms of genotype distribution (p=0.07, p=0.53, respectively). Control groups of lung and prostate cancer were in Hardy-Weinberg equilibrium (p=0.87 and p=0.41, respectively). To determine the protective effect against lung cancer among individuals with the -463A allele, G/A and A/A genotypes were combined. Comparison of the G/G and G/A + A/A genotypes between the lung cancer cases and control groups showed a statistically significant relationship (p=0.032, OR=0.60, 95% CI 0.38-0.95). No gender-specific difference was found in terms of genotype distribution between the lung cancer patients and the controls (female, p=0.20; male, p=0.34). In the case of smokers, a difference in genotype distribution between the lung cancer patients and the controls was statistically significant (p=0.02), although this difference was not statistically significant for non-smokers (p=0.90). Overall, no statistically significant difference was found between the prostate cancer cases and the controls in terms of genotype combination (p=0.46, OR=0.83, 95% CI 0.51-1.36). Additionally, in smokers and non-smokers, no significant relationship was determined between the prostate cancer patients and the control population (p=0.21, p=0.91, respectively). These results suggest that the MPO -463A allele significantly contributes to a protective effect overall and in smokers against lung cancer.

An investigation of the relationship between SULT1A1 Arg213His polymorphism and lung cancer susceptibility in a Turkish population

Human sulfotransferase 1A1 (SULT1A1), the most expressed isoform of the phenol SULT1 subfamily, is an important member of sulfotransferase superfamily. A transition, G to A at position 638, in SULT1A1 gene, results in Arg213His change. This single nucleotide polymorphism reduces the activity and thermostability of SULT1A1 enzyme. Thus, in the present study the relationship between SULT1A1 Arg213His polymorphism and lung cancer was investigated. One hundred and six case and 271 control samples were studied using PCR‐RFLP. There was no significant difference in genotype and allele distribution between lung cancer and control populations (p = 0.07; p = 0.06, respectively). Compared with the SULT1A1*1/SULT1A1*1 genotype the variant SULT1A1 genotype (SULT1A1*1/SULT1A1*2 or SULT1A1*2/SULT1A1*2) was associated with a significantly increased lung cancer risk in cases (p = 0.027). In male populations, there was no significant difference between case and controls (p = 0.313). In female populations, however, this difference was found to be significant (p = 0.04). In smoker and non‐smoker populations, no significant relationship was evident between lung cancer and control population (p = 0.170, p = 0.065, respectively). Statistical analyses of histological types of lung cancer in comparison with the control individuals indicated a significant difference between SULT1A1 Arg213His polymorphism and SCC (p = 0.027) and other types of cancer (p = 0.037), except SMCC (p = 0.854). Copyright

Microsomal epoxide hydrolase polymorphisms.

Microsomal epoxide hydrolase plays a dual role in the activation and detoxification of carcinogenic compounds. Two polymorphic sites have been described in exons 3 and 4 of the microsomal epoxide hydrolase gene that change tyrosine residue 113 to histidine (Tyr113His) and histidine 139 to arginine (His139Arg), respectively. The exon 3 polymorphism reduces enzyme activity by approximately 50%, whereas the exon 4 polymorphism causes a 25% increase in activity. In the present study, the distribution of these polymorphisms in a Turkish population including 625 unrelated healthy individuals was examined using a PCR-RFLP method. The observed genotype frequencies of microsomal epoxide hydrolase exon 3 were 54, 38 and 8% for Tyr113Tyr, Tyr113His and His113His, respectively. Exon 4 genotype frequencies were found to be 69, 29 and 2% for His139His, His139Arg and Arg139Arg, respectively.

The acute and chronic toxic effect of cypermethrin, propetamphos, and their combinations in rats

This study was aimed at determining the acute and chronic toxic effects of cypermethrin, propetamphos, and combined cypermethrin and propetamphos. Four groups, each comprising 10 animals, were established for the acute (a) and chronic (b) toxicity trials, and in total, 80 male Wistar albino rats were used. In the acute toxicity trial, the first group was maintained for control purposes, and groups 2a, 3a, and 4a were administered only once with 80 mg/kg.bw of cypermethrin, 25 mg/kg.bw of propetamphos and 80 mg/kg.bw of cypermethrin combined with 25 mg/kg.bw of propetamphos, respectively, by gavage directly into the stomach. In the chronic toxicity trial, the first group was also maintained for control purposes, while groups 2b, 3b, and 4b were administered daily with 12 mg/kg.bw of cypermethrin, 4 mg/kg.bw of propetamphos, and 12 mg/kg.bw of cypermethrin combined with 4 mg/kg.bw of propetamphos respectively, by gavage directly into the stomach for 60 days. Blood and tissue (liver, kidney, brain, spleen, and testis) samples were taken 24 h after pesticide administration in the acute toxicity trial and at the end of day 60 in the chronic toxicity trial. Oxidative stress (MDA, NO, SOD, CAT, GSH‐Px, and G6PD) parameters, serum biochemical parameters (glucose, triglyceride, cholesterol, HDL, LDL, BUN, creatinine, AST, ALT, ALP, protein, and albumin) and hepatic drug‐metabolizing parameters (CYP2E1, CYPB5, CYTC, GST, and GSH) were investigated in the samples. When administered either alone or in combination, both pesticides inhibited the antioxidant enzymes and increased MDA and NO levels. For the drug‐metabolizing parameters investigated, particularly in the chronic period, either increase (CYP2E1, CYPB5, and CYTC) or decrease (GST and GSH) was observed. Furthermore, some negative changes were detected in the serum biochemical parameters. In result, cypermethrin and propetamphos combinations and long‐term exposure to these combinations produced a greater toxic effect than the administration of these insecticides alone.

Is there a relation between Murine double minute 2 T309G polymorphism and lung cancer risk in the Turkish population

Abstract Introduction: Association between Murine double minute 2 T309G polymorphism and lung cancer risk has been investigated in several populations, but results of these studies are inconsistent. We aimed to investigate the effect of Murine double minute 2 T309G polymorphism on development of lung cancer in a Turkish population. Methods: Total 200 subjects including 100 patients and 100 controls were analyzed and used polymerase chain reaction and restriction fragment length polymorphism methods for genotyping analysis of the polymorphism. Results: We found that smokers compared with non-smokers have approximately eight fold higher lung cancer risk [p=0.0001, OR=8.27 (4.02–16.9)]. Frequency of GG genotype was higher in patients than in controls, but this ratio was not significant (χ2=3.5, p=0.17). Genotype distribution of the polymorphism was not different neither patients with non-small cell lung cancer nor patients with small cell lung cancer (χ2=2.89, p=0.57). We analyzed together with demographic feature (except smoking habit), clinicopathological findings and genotype frequencies of this polymorphism, and any association with lung cancer risk was not obtained. Conclusion: No correlation between Murine double minute 2 T309G polymorphism and lung cancer risk was detected in this Turkish population. Özet Giriş: Çeşitli popülasyonlarda akciğer kanseri riski ile Murine double minute 2 T309G polimorfizminin birlikteliği incelenmiş, fakat bu çalışmaların sonuçları arasında tutarsızlık olduğu görülmüştür. Bu çalışmada, bir Türk popülasyonunda akciğer kanserinin gelişimi üzerine Murine double minute 2 polimorfizminin etkisini araştırmayı amaçlanmıştır. Yöntemler: Bu çalışmada, 100 hasta 100 kontrolden oluşan toplam 200 örnek incelenmiş ve bu polimorfizmin genotip analizi için polimeraz zincir reaksiyonu ve restriksiyon fragment uzunluk polimorfizmi yöntemleri kullanılmıştır. Bulgular: Çalışmada sigara içmeyenlerle karşılaştırıldığında sigara içenlerin yaklaşık olarak sekiz kat daha fazla akciğer kanseri gelişme riskine sahip oldukları bulunmuştur [p=0.0001, OR=8.27 (4.02–16.9)]. GG genotipi kontrollere oranla hastalar arasında daha yüksek oranda bulunmuştur fakat bu oran anlamlı değildir (χ2=3.5, p=0.17). Bu polimorfizmin genotip dağılımı ne küçük hücreli akciğer kanseri olan hastalarda ne de küçük hücreli olmayan akciğer kanseri olan hastalarda farklılık göstermediği bulunmuştur (χ2=2.89, p=0.57). Polimorfizmin genotip sıklıkları, klinikopatolojik bulgular ve demografik özellikler (sigara alışkanlığı hariç) birlikte değerlendirilmiş ve bu bulgular arasında akciğer kanseri riski ile herhangi bir ilişki elde edilememiştir. Sonuç: Bu Türk popülasyonunda akciğer kanseri riski ve Murine double minute 2 T309G polimorfizmi arasında bir korelasyon belirlenememiştir.