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Dicyclopentadiene (DCPD) is an olefinic hydrocarbon which is manufactured and imported into the European Union (EU) at greater than 1000 tons per year. Concerns related to fetotoxic effects observed in reproductive toxicity studies at high doses led the REACH registrants to self-classify DCPD as a Category 2 reproductive toxicant under the EU CLP Regulation. DCPD was also reviewed in the European Union in the frame of an ongoing European Chemical Agency (ECHA) Community Rolling Action Plan (CoRAP) procedure and under the French National Strategy on Endocrine Disruptors (SNPE). To elucidate whether the developmental effects may be triggered by an endocrine mode of action, the Lower Olefins Sector Group (LOSG) of the European Chemical Industry Council (CEFIC) formed an ad hoc expert team to review the available scientific information pertaining to the potential endocrine activity and adversity of DCPD. Existing experimental data was complemented with structure activity modelling using ECHA-recommended (Q)SAR tools. Overall, considering the available information from (Q)SAR, mechanistic in vitro and in vivo studies, no indication of endocrine-mediated adversity was found. Hence, the available evidence supports the conclusion that DCPD does not cause developmental toxicity via an endocrine mode of action. Further work is ongoing to support this conclusion.

Occupational exposure to benzene at levels of 10 ppm or more has been associated with increased risk of acute myeloid leukaemia (AML). The mode of action (MOA) for AML development leading to mortality is anticipated to include multiple earlier key events, which can be observed in hematotoxicity and genetic toxicity in peripheral blood of exposed workers. Prevention of these early events would lead to prevention of the apical, adverse outcomes, the morbidity and mortality caused by the myelodysplastic syndrome (MDS) and AML.. Incorporation of key event information should modify the risk model, but few modification approaches have been suggested. To that end, two approaches to risk model modification are described that use sub-linear and segmented linear increases in risk below key events, while maintaining a linear increase in AML mortality risk beginning at 2 ppm, the lowest observed adverse effect concentration (LOAEC) identified for hemato- and geno- toxicity in high quality studies of human occupational exposure. Below 2 ppm two different modification approaches to quantitative risk models were applied: a continuously decreasing slope model and a segmented modification in slope. These two approaches provide greater flexibility to incorporate MOA information in risk model development and selection.

This paper derives an occupational exposure limit for benzene using quality assessed data. Seventy-seven genotoxicity and 36 haematotoxicity studies in workers were scored for study quality with an adapted tool based on that of Vlaanderen et al 2008 (Environ Health. Perspect. 116 1700-5). These endpoints were selected as they are the most sensitive and relevant to the proposed mode of action and protecting against these will protect against benzene carcinogenicity. Lowest and No- Adverse Effect Concentrations (LOAECs and NOAECs) were derived from the highest quality studies (i.e. those ranked in the top tertile or top half) and further assessed as being “more certain” or “less certain”. Several sensitivity analyses were conducted to assess whether alternative “high quality” constructs affected conclusions. The lowest haematotoxicity LOAECs showed effects near 2 ppm (8h TWA), and no effects at 0.59 ppm. For genotoxicity, studies also showed effects near 2 ppm and showed no effects at about 0.69 ppm. Several sensitivity analyses supported these observations. These data define a benzene LOAEC of 2 ppm (8h TWA) and a NOAEC of 0.5 ppm (8h TWA). Allowing for possible subclinical effects in bone marrow not apparent in studies of peripheral blood endpoints, an OEL of 0.25ppm (8h TWA) is proposed., Shorter and updated version of this article

Understanding the Mode of Action (MOA) for a chemical can help guide decisions in development of Occupational Exposure Limits (OELs). Where sufficient information exists, it can provide the OEL developer the basis for selecting either a health-based or risk-based approach. To support the development of an OEL for benzene, scientific information relevant to MOA assessment for risk-based and health-based OEL approaches was reviewed. Direct-acting mutagenicity was considered as a basis for a risk-based OEL, versus MOAs consistent with a health-based approach: indirect mutagenicity via topoisomerase II inhibition, indirect mutagenicity via reactive oxygen species generation, or an immune-based bone marrow dysfunction. Based on the evidence against direct DNA reactivity, threshold expectations for remaining MOAs, and evidence for dose rate affecting acute myeloid leukemia and myelodysplastic syndrome risk, the weight of evidence favors a health-based OEL approach. In the case of benzene, development of an OEL based on observations of earlier key events (i.e., hematologic changes and genetic toxicity) is anticipated to provide protection from later adverse outcomes such as leukemia.

Background: Individual differences in the activity of enzymes that metabolize xenobiotics can impact health and disease. Beta-2 adrenoreceptor (ADRB2) is a functional G-coupled protein expressed in the vascular endothelium of lungs, alveolar walls, and the ganglions of cholinergic nerves which induces bronchodilation in response to catecholamines. Glutathione S-Transferase-P1 (GSTP1) is a candidate pi class GST gene, which controls pi class glutathione S-transferase activity. Aims: In this study we determined the relationship between the ADRB2 Arg16Gly polymorphism and GSTP1 polymorphisms, involved in bronchodilator response and oxidative stress, respectively, with susceptibility to asthma. Methods: In this study, 129 asthmatic patients and 127 healthy control cases were recruited to determine ADRB2 and GSTP1 genotypes by allele-specific polymerase chain reaction and restriction fragment length polymorphism assays, respectively. Results: The ADRB2 genotype frequencies of the patients and control cases were found to be 10.9% (Arg16Arg), 48.8% (Arg16Gly), and 40.3% (Gly16Gly) and 24.4% (Arg16Arg), 36.2% (Arg16Gly), and 39.4% (Gly16Gly), respectively. GSTP1 genotype frequencies of patients and control cases were found to be 55% (Ile105Ile), 43.4% (Ile105Val), and 1.6% (Val105Val) and 75.6% (Ile105Ile), 22% (Ile105Val), and 2.4% (Val105Val), respectively. In the case of the GSTP1 gene, we found statistically significant differences in the genotype frequency of Ile105Val and the allele frequency of Val105 in the asthmatic group compared with the controls. Moreover, we observed a relationship between allele frequencies and clinical phenotypes including atopia nocturnal dyspnea, and steroid dependency in the asthmatic patients. Conclusion: Our results suggest that the GSTP1 Ile105Val polymorphism may be linked to the severeness of airway dysfunction.

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has pivotal roles in neuronal survival, proliferation, and synaptic plasticity in the brain. Both clinical and pharmacological studies have implicated the common single nucleotide polymorphism (SNP) at position 196, Val66Met in the pathophysiology of major depressive disorder (MDD), and antidepressant response. However, inconsistent results were found between Val66Met (rs6265) polymorphism and treatment response phenotypes in genetic association studies. The functional Val66Met polymorphism and seven other tagging SNP markers selected to capture the major allelic variations across BDNF locus were analyzed in depressed patients, treated with antidepressants, and 76 control patients. Two hundred and six patients with Diagnostic and Statistical Manual of Mental Disorders-IV MDD were recruited for this study and genotyped for eight BDNF tagging SNPs (rs11030096, rs925946, rs10501087, rs6265, rs12273363, rs908867, rs1491850, and rs1491851) to investigate the functional impact of genotypes/haplotypes in the susceptibility of depression and on treatment response. None of the eight SNPs, including the rs6265, were significantly associated with MDD after permutation correction. However, we found an association for rs10501087, rs6265 with nonresponse to antidepressant treatment (corrected permutation P: 0.03599; 0.0399 and power: 0.1420; 0.1492, respectively). Analysis of each two-marker, three-marker, and four-marker sliding window haplotypes showed significance in haplotype combinations. Especially rs10501087 (C), rs6265 (A), and rs1491850 (C) together or with the other SNP haplotypes showed a similar pattern in all treatment response phenotypes. Despite the limited power of analysis, our results suggest that these three SNPs may play a role in antidepressant treatment response phenotypes in MDD. Int Clin Psychopharmacol 26:1-10 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

The presenting study was investigated the associations between individual susceptibility and cigarette smoke on maternal chromosomal damage and neonatal birth growth in smoking mothers since little known about genetic susceptibility to cigarette smoke in relation to adverse pregnancy outcome such as birth growth. Sixty-one pregnant women who completed a questionnaire at Ankara Education and Research Hospital, Department of Obstetrics and Gynecology have enrolled in this study. GSTM1 and OGG1 ser326Cys gene polymorphisms were analysed by RFLP-PCR (Restriction Fragment Length Polymorphism-Polymerase Chain Reaction) as possible genetic factors affecting susceptibility to such health effects of smoking and chromosomal damage was performed by chromosomal aberration assay (CAA) in maternal blood lymphocytes. Maternal self-reported history of pregnancy smoking was informed by questionnaire declaration. Our results showed that maternal smoking had significant effect on chromosomal damage, birth weight, and length. The frequencies of CA in smokers was significantly higher than that of the nonsmokers (3.46 +/- A 2.06 and 2.00 +/- A 1.3, P = 0.001). Birth weight and length in smokers were significantly higher that of nonsmokers (3,355 g and 49.57 cm, P = 0.001; 3,639 g and 50.79 cm, P = 0.002). On the other hand, there was a slightly increased in the frequencies of CA and reduction birth weight and length in GSTM1 null and length in OGG1 variant genotypes, those differences were not statistically significant (P > 0.05); likely due to small sample size. Larger sample size needs to reach significance.

So far, associations between serotonergic neurotransmission pathways and suicidality have been reported. The aim of our study was to investigate the role of genetic polymorphisms and gene-gene interactions of the 5-HTR1A and the 5-HTR2A gene on suicide risk and/or a personal history of suicide attempts. A total of 374 major depressive disorder patients, adequately treated with antidepressants for at least 4 weeks, were collected in the context of a European multicentre study on treatment-resistant depression. We assessed suicidality using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D17 and remission as HAM-D7 after 4 weeks of adequate antidepressant treatment. The 5-HTR1A rs6295 (C-1019G) single nucleotide polymorphism (SNP) and the 5-HTR2A rs7997012, rs6313, rs643627 and rs17288723 SNPs were selected for genotyping. Using logistic regression analyses, no association (P

PubMed: 17132602 Pharmacogenetics is the study of genetic variations that cause a variable drug response characterized by alteration in drug metabolism or in pharmacodynamics. The polymorphisms in genes encoding receptors relevant to treatment cause variation in sensitivity to many drugs. ?2 Adrenoceptor genetic variation contributes to regulation of blood pressure and hemodynamic changes by mediating peripheral vasodilatation. Laryngoscopy and tracheal intubation associated with hemodynamic changes. Although there are four nonsynomic single-nucleotide polymorphisms (SNPs) of ?2 adrenoceptor gene, codon 16 (Arg16Gly) and codon 27 (Gln27Glu) SNPs are both common and functionally important. In this paper, the authors investigated the ?2 adrenoceptor Gly16 and Glu27 SNPs in response to drugs relevant to anesthesia and how these SNPs impacted upon the cardiovascular phenotypes. The authors measured arterial systolic and diastolic blood pressure, heart rate, and rate-pressure product before induction of anesthesia and 1 min following laryngoscopy and tracheal intubation. Genomic DNA was amplified and genotyped using allele-specific polymerase chain reaction (ASPCR) and restriction fragment length polymorphism (RFLP) assays, respectively. When the authors compared hemodynamic results according to genotypes, the patients with Gln homozygote allele at codon 27 exhibited significant increase of heart rate than patients with Glu allele after laryngoscope and tracheal intubation. Copyright © American College of Toxicology.

The association between the cytochrome P-450 1B1 (CYP1B1) Val432Leu polymorphism and breast cancer was assessed through a meta-analysis of all published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database ( www.upci.upmc.edu/research/ccps/ccontrol/g_intro.html ). GSEC is a collaborative project that gathers information on studies of metabolic gene polymorphisms and cancer. Thirteen articles were included in the meta-analysis (14,331 subjects; 7,514 cases, 6,817 controls); nine data sets were included in the pooled analysis (6,842 subjects; 3,391 cases, 3,451 controls). A summary meta- or pooled estimate of the association between the CYP1B1 Val432Leu polymorphism and breast cancer could not be calculated because of statistically significant heterogeneity in the point estimates among studies. No association between the CYP1B1 Val432Leu polymorphism and breast cancer was observed in Asians (for Val/Val and Val/Leu combined, odds ratio (OR) = 1.0, 95% confidence interval (CI): 0.8, 1.2). An inverse association was observed in populations of mixed/African origin (OR = 0.8, 95% CI: 0.7, 0.9). The pooled analysis suggested a possible association in Caucasians (for Val/Val and Val/Leu combined, OR = 1.5, 95% CI: 1.1, 2.1), with effect modification across age categories. The observed effect of age on the association in Caucasians indicates that further studies are needed on the role of CYP1B1 Val432Leu in estrogen metabolism according to age, ethnicity, and menopausal status. This project was supported by grant OC B20.001 from the European Program for Co-Operation in Science and Technology (COST) (Action B20) and by the ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility) Network of Excellence (European Union Sixth Framework Programme for Research and Development).

Within mitochondria, manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species (ROS). An alanine-9valine (Ala-9Val) polymorphism in the mitochondrial targeting sequence of MnSOD has been described and has recently been associated with risk of human breast cancer. Our present case-control study was performed to explore the association between MnSOD genetic polymorphism and individual susceptibility to breast cancer. Ala-9Val polymorphism in the signal sequence of the protein for MnSOD was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a study population. There was no significant difference in risk for breast cancer development between patients positive and negative for the MnSOD Ala allele with adjusted odds ratio (OR): 0.86 (95% confidence interval (CI) 0.43 to 1.72). When MnSOD Ala was combined with either cytochrome P450 1B1 CYP1B1*1 and catechol O-methyltransferase COMT-L (V158M) genotypes, the risk for developing breast cancer was significantly increased in patients with a body mass index (BMI) greater than 24 kg m(-2) (OR: 1.42 (95%CI = 1.04-1.93)). Copyright (C) 2004 John Wiley Sons, Ltd.

Purpose: Mood disorders are present in more than 90% of suicides, and a genetic vulnerability to suicidality is well established. Numerous lines of evidence relate the transcription factor Cyclic adenosine monophosphate Response Element Binding protein (CREB1) to suicide, and to the aetiology of major depressive disorder (MDD). Our aim was to test for association between CREB1 single nucleotide polynnorphisms (SNPs) and both suicide risk (SR) and a personal history of suicide attempt (SA) in MDD patients. Materials and Methods: A sample of 250 MDD patients collected in the context of a European multicenter resistant depression study and treated with antidepressants over a period of at least 4 weeks were genotyped for five CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). To assess suicidality, the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D) were applied. Results: Neither single-marker nor haplotypic association were found between SR and/or a personal history of SA with any of the investigated SNPs after multiple testing correction. For females, an association between rs2709376 and a personal history of SA was found (p = 0.016), however not resisting multiple testing correction. Conclusions: Although we found significant CREB1 single marker association with a personal history of SA in female MDD patients, this finding could not be confirmed in haplotypic analyses after multiple testing correction. Larger well-defined cohorts are required to confirm or refute a possible association of CREB1 and SA in female MDD patients.

Epidemiological studies indicate that most risk factors for breast cancer are related to reproductive and hormonal factors. Estrogen has been proposed to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). Because of the important role of cytochrome P450 IBI (CYP1B1) and catechol O-methyltransferase (COMT) in mammary estrogen and carcinogen metabolism, we examined the CYP1B1 and COMT genes to determine whether genetic variations could account for inter-individual differences in breast cancer. In this case-control study, we determined CYP1B1 and COMT genotypes in 84 breast cancer patients and 103 healthy unrelated women controls from a Turkish population. In the case of CYP1B1, we genotyped CYP1B1*3 (L432 V) allele. We found that carriers of the CYP1B1*3 allele were more frequent among breast cancer patients with adjusted odds ratio (OR) for age, age at menarche, age at first full-term pregnancy, body mass index (BMI) and smoking status of 2.32 (95% confidence interval 1.26-4.25) associated with the allele. However, this allele appeared to be a significant factor for susceptibility only in patients with a BMI greater than 24 kg/m(2). Menopausal status did not appear to affect susceptibility. In the case of COMT, there was no significant difference in susceptibility for breast cancer development between patients with low activity COMT-L (V 158 M) allele and high activity COMT-H allele, and susceptibility was not affected by menopausal status, BMI or CYP1B1 genotype. We conclude that the CYP1B1*3 allele appears to be a factor for susceptibility to breast cancer in Turkish women 2 especially those with a BMI greater than 24 kg/m(2).

Background: Cytogenetic biomarkers are most frequently used well-established endpoints in human population studies with their sensitivity for measuring exposure to genotoxic agents. They have an important role as early predictors of cancer risk. Identification of individual genotypes of metabolic gene polymorphisms helps to understand the modulation of cancer susceptibility by environmental exposures, such as cigarette smoking and other lifestyle factors. Aim: To evaluate individual susceptibility to chemicals, we determined individual DNA damage related to glutathione S-transferase (GST) genotypes (GSTM1, GSTT1, and GSTP1) in a Turkish population. Methods: Peripheral blood lymphocytes (PBL) and DNA samples of 127 subjects were analyzed for the presence of DNA damage, using single-cell gel electrophoresis (the Comet assay), and for cytogenetic parameters (chromosomal aberrations [CAs], bleomycin-induced CA, and a cytokinesis-blocked micronucleus assay), and the polymerase chain reaction/restriction fragment length polymorphism method, respectively. Results: Individuals carrying a GSTT1-null allele showed higher frequencies of CA and micronucleus (MN) (p = 0.026, p = 0.003, respectively), whereas the GSTM1-null and GSTP1 mutant genotypes did not show any differences in cytogenetic parameters. Our findings demonstrated that none of the lifestyle factors (smoking, alcohol drinking, dietary habits, vitamin intake, and physical activity), except for vitamin intake (p = 0.002), were significantly associated with the studied cytogenetic parameters. Conclusion: Our results suggest that the GSTT1 gene polymorphism may influence the baseline cytogenetic frequency in a healthy population.

The aim of the present study was to investigate the role of some polymorphisms in GSTs ( GSTM1 , GSTT1 and GSTP1 ) which are very important protective mechanisms against oxidative stress and in OGG1 gene which is important in DNA repair, against the risk of type 2 diabetes mellitus (T2DM). 127 T2DM and 127 control subjects were included in the study. DNA was extracted from whole blood. Analyses of GSTM1 and GSTT1 gene polymorphisms were performed by allele specific PCR and those of GSTP1 Ile105Val and OGG1 Ser326Cys by PCR‐RFLP. Our data showed that GSTM1 null genotype frequency had a 2–6 times statistically significant increase in a patient group (OR = 3.841, 95% CI = 2.280–6.469, p GSTT1 null/positive and GSTP1 Ile105Val genotypes was observed. When T2DM patients with OGG1 Ser326Cys polymorphism were compared with patients with a wild genotype, a 2–3 times statistically significant increase has been observed (OR 1.858, 95% CI = 1.099–3.141, p = 0.021). The combined effect of GSTM1 null and OGG1 variant genotype frequencies has shown to be statistically significant. Similarly, the risk of T2DM was statistically increased with GSTM1 null (OR = 3.841, 95% CI = 2.28–6.469), GSTT1 null + GSTP1 (H + M) (OR = 4.118, 95% CI = 1.327–12.778) and GSTM1 null + OGG1 (H + M) (OR = 3.322, 95% CI = 1.898–5.816) and GSTT1 null + OGG1 (H + M) (OR = 2.179, 95% CI = 1.083–4.386) as compared to the control group. According to our study results, it has been observed that the combined evaluation of GSTM1 – GSTT1 – GSTP1 and OGG1 Ser326Cys gene polymorphisms can be used as candidate genes in the etiology of T2DM, especially in the development of T2DM.

Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D a parts per thousand currency sign 17 and remission as HAM-D a parts per thousand currency sign 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions.

Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study. They were genotyped for COX-2 and OXTR SNPs. Treatment resistance (according to two different definitions), response and remission were recorded. We did not observe any association between the genotypes or alleles of the selected SNPs within COX-2 and OXTR genes and treatment resistance, response and remission in the whole sample. Our results are consistent with those of some studies but not with those of other ones. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, and different definitions of treatment resistance. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Psychiatry is a specialty where the application of pharmacogenomics approaches is made to the study of inter-individual differences in response to antidepressants. It is highly applied for improving patient treatment. Major depressive disorder (MDD) is a common and complex disorder resulting from genetic and environmental interactions. Less than 40% of patients with MDD achieve remission, and even after several treatment trials, one in three patients do not fully recover from MDD. Many clinical and genomic association studies suggested that the catechol-O-methyltransferase (COMT) gene region was an important genetic locus for psychiatric disorders, because of the proposed relationship between its function in catecholaminergic neurotransmission and individual response to antidepressants, and vulnerability to psychiatric disorders. Although a number of COMT single nucleotide polymorphisms (SNPs) were observed, the Val108/158Met (rs4680) polymorphism in exon 4 resulted in a change in the enzyme structure which has been intensively investigated in relation to its role of enzyme activity and processes of prefrontal cortex functions in cognition. As serotonin interacts with dopamine and dopamine availability is influenced by COMT SNPs, an association between the COMT gene and response to treatment, based on the various pharmacogenetics/pharmacogenomics studies about COMT gene published to date, is explored in this overview.

Head and neck squamous cell carcinoma is the fifth most common cancer type worldwide. Even though it is known that the most important environmental aetiological factors for head and neck cancer (HNC) development are tobacco and alcohol, genetic susceptibility is also thought to be important. The use of biomarkers of chromosomal damage due to genetic instability in order to predict risk of cancer as well as to identify high-risk individuals is imperative. We have investigated genetic damage in patients having HNC (n = 59) and their first-degree relatives (FDRs) (n = 34) with a biomarker in two different tissues; the micronucleus (MN) test in peripheral blood lymphocytes and in exfoliated buccal cells. The mean (standard deviation) levels of MN frequencies (parts per thousand) in lymphocytes of patients, relatives and controls were 27.10 (9.52), 14.09 (5.13) and 9.00 (6.87), respectively. The mean (standard deviation) levels of MN frequencies (parts per thousand) in exfoliated buccal cells of patients, relatives and controls were 2.87 (1.16), 1.38 (0.85) and 1.23 (0.93), respectively. Our results indicated that spontaneous genetic damage in lymphocytes of patients having HNC was significantly higher than that of controls (P < 0.01) and thus genetic instability appeared to exist in lymphocytes of cancer patients. Similar findings were obtained for exfoliated buccal cell MN frequencies of cancer patients (P < 0.01). We observed that the FDRs of patients having HNC showed significantly higher chromosomal damage in terms of MN frequencies in lymphocytes when compared with those of controls (P < 0.05), thus reflecting an increased susceptibility to HNC in FDRs. However, for buccal cell MN frequencies, we could not demonstrate enhanced genetic instability in the FDRs of patients having HNC.

The 5HT2A (5HTR2A) and 5HT1A receptor (5HTR1A) genes are plausible candidate genes for major depressive disorders. Two single nucleotide polymorphisms, the rs7997012 in 5HTR2A and the -1019C/G in 5HTR1A, were analyzed in 206 patients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder. Patients were retrospectively characterized for clinical response to antidepressant treatment. We found a significant difference in the rs7997012 allele frequency between resistant and nonresistant patients. However, following the Bonferroni correction we could not find any association between this single nucleotide polymorphism and treatment resistance phenotype. Nevertheless, given the limited power of our analysis, we are not able to conclude that these results reflect a lack of association. Additional studies are needed to confirm or to disprove our result. Int Clin Psychopharmacol 25: 228-231 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Catechol-O-methyltransferase (COMT) has been suggested to be involved in the pathogenesis and pharmacological treatment of affective disorders. The nonsynonymous single nucleotide polymorphism (SNP) in exon 4 (Val108/158Met; rs4680) influences the COMT enzyme activity. Inconsistent results were found between Val158Met polymorphism (rs4680) and treatment response phenotypes in genetic association studies. However, the haplotype combinations of alleles at the Val108/158Met SNP with the other synonymous SNPs in the COMT gene region have shown association between enzyme activity/amount and COMT-dependent phenotypes. We carried out this study to define the functional impact of COMT genotypes/haplotypes on susceptibility and on treatment response phenotypes of major depressive disorder (MDD). Three hundred and ninety-six patients with MDD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [(DSM)-IV] and 295 healthy controls were recruited for this study and genotyped for the seven COMT SNPs (rs2075507, rs737865, rs6269, rs4633, rs4818, rs4680, and rs165599). This is the first study with all these SNPs to investigate for MDD and treatment response phenotypes. Our results show that none of the seven SNPs, including the rs4680, was significantly associated with MDD after permutation correction in single SNP analyses. Although several haplotype combinations showed significance, the combinations of G-T-G-G haplotype for rs6269, rs4633, rs4818 and rs4680 were only present in the MDD group (G-T 4.5%, corrected sim P = 0.0001; G-T-G 3.87%, corrected sim P = 0.001; G-T-G-G 3.3% corrected sim P=0.0025). In the treatment response phenotypes, the GG genotype of the rs2075507 SNP ( located in the promoter region of MB-COMT) was less common in resistant patients in a single SNP analysis with low corrected sim P=0.052 and power=0.086. However, in the haplotype analysis, the haplotypes of exonic SNPs, rs4633, rs4818, and rs4680, were related to the treatment response phenotypes investigated, especially the phenotype of the response to antidepressant treatment. The C-C-A haplotype of these SNPs was overrepresented (almost four-and eight-fold) in the responders compared with the nonresponders and controls, respectively, after Bonferroni correction (corrected sim P = 0.048, 0.0001, respectively). Both nonsynonymous and synonymous SNPs within haplotypes may be more relevant than the single SNP in conferring MDD susceptibility and treatment response phenotypes. Despite the limited power of our analysis, this finding suggests that the polymorphic COMT gene that influences catecholaminergic neurotransmission may play a role in the individual response to antidepressants. Int Clin Psychopharmacol 25: 218-227 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Gemcitabine and other cytidine antimetabolites require metabolic activation by phosphorylation. Deoxycytidine kinase (DCK) and cytidine monophosphate kinase (CMPK) catalyze these reactions. We have applied a genotype-to-phenotype strategy to study DCK and CMPK pharmacogenomics. Specifically, we resequenced DCK and CMPK using 240 DNA samples, 60 each from African-American, Caucasian-American, Han Chinese-American, and Mexican-American subjects. We observed 28 DCK polymorphisms and 28 polymorphisms in CMPK, 33 of which were novel. Expression in COS-1 cells showed that variant allozyme enzyme activities ranged from 32 to 105% of the wild type (WT) for DCK and from 78 to 112% of WT for CMPK--with no significant differences in apparent K(m) values for either enzyme except for a DCK Val24/Ser122 double variant allozyme. Relative levels of DCK and CMPK immunoreactive protein in the COS-1 cells paralleled relative levels of enzyme activity and were significantly correlated for DCK (R(p) = 0.89, P = 0.0004) but not for CMPK (R(p) = 0.82, P = 0.095). The results of an analysis of DCK and CMPK structural models were compatible with the observed functional consequences of sequence alterations in variant allozymes. We also confirmed that the CMPK protein expressed in COS-1 cells and in a rabbit reticulocyte lysate was 196 rather than 228 amino acids in length. In summary, we determined common sequence variations in DCK and CMPK and systematically evaluated their functional implications. These gene sequence differences may contribute to variations in the metabolic activation of gemcitabine and other cytidine antimetabolites.

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Humans are routinely exposed to mutagenic and carcinogenic chemicals. These chemicals can form DNA adducts in vivo and thus lead to DNA damage. The integrity of most of the so-damaged DNAs is typically restored as a consequence of the action of certain DNA-repairing enzymes. In several DNA repair genes, polymorphisms may result in reduced repair capacity, which has been implicated as a risk factor for various types of cancer. XRCC1 is a base-excision repair protein that plays a central role in the repair of DNA base damage and strand breaks. Amongst the known genetic polymorphisms of the DNA-repair genes, X-ray repair cross-complementing groups 1 and 3 ( XRCC1 and XRCC3) have been studied most commonly. Inconsistent results have been reported regarding the associations between the Arg399Gln (exon 10) polymorphism of XRCC1 and either functional significance or the risk of tobacco-associated cancers. The Gln allele of this polymorphism was associated with higher levels of DNA adducts. Therefore we genotyped one of the polymorphism of XRCC1, Gln allele. The frequency of the polymorphic alleles varies among populations, suggesting an ethnic distribution of genotypes. There has been no information on interindividual variability of Arg399Gln genotype in the Turkish population. Due to the association between the Arg399Gln polymorphism of XRCC1 and the risk of tobacco-associated cancers, we preferred to evaluate the allelic frequencies of Arg399Gln genotype than the other polymorphisms in XRCC1 gene in healthy Turkish population by polymerase chain reaction–restriction fragment polymorphism (PCR-RFLP) analysis to enable to show interindividual differences and compare to other populations.

Oxidative DNA damage, caused by either endogenous or exogenous sources of reactive oxygen species (ROS), has been linked to aging, chronic degenerative diseases, inflammatory diseases and cancers. 8-Hydroxydeoxyguanine (8-OHdG) is a major lesion produced by ROS. Among various types of DNA base modifications, 8-OHdG has been the most widely studied and is considered a key biomarker of oxidative DNA damage. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key component of the base excision repair (BER) pathway and catalyzes the removal of 8-OHdG. Ethnic and inter-individual differences in hOGG1 activity and several kinds of polymorphisms at the hOOG1 gene locus have been observed in the different populations studied so far. Since no information is available on the inter-individual variability of the hOGG1 genotype in the Turkish population, we genotyped 206 healthy, unrelated Turkish individuals. The allelic frequencies of the hOGG1 gene in the Turkish population were found to be 0.50, 0.41 and 0.09 (Ser/Ser, Ser/Cys and Cys/Cys, respectively). Our results are similar to those for Caucasians studied previously but are different from Asian populations. It seems that there is a growing need for extensive genotype studies with respect to the hOGG1 gene due to its importance to various types of cancer and to smoking habits.

Increased exposure to environmental carcinogens, including several aromatic and heterocyclic amines (HAs), is suspected to be one factor contributing to incidence of breast cancer. The N-acetyltransferase 2 ( NAT2) acetylation polymorphism have been associated with a number of drug-induced toxicities and cancer in various tissues, resulting from decreased capacity to activate/deactivate several aromatic amine, hydrazine drugs, as well as HA carcinogens. Ethnic differences exist in NAT2 genotype frequencies, which may be a factor in cancer incidence. Our present case-control study in Turkey was performed to explore the association between NAT2 genetic polymorphism and individual susceptibility to breast cancer. The NAT2 genotypes (* 4, * 12A, *5 A, * 5B, * 5C, * 6, * 7) were determined using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay in 84 breast cancer patients and 103 healthy controls, and 50% and 56.3%, respectively, were found to be slow acetylator genotypes. There was no significant difference in risk for breast cancer development among patients with rapid and slow acetylators, with adjusted odds ratio 0.78 (95% confidence interval 0.44 to 1.38). Also, risk was not affected by different variables. To our knowledge, this is the first genetic study on the association of NAT2 genotypes with breast cancer in the Turkish population, and this finding showed that NAT2 polymorphism does not play an important role in breast cancer risk of Turkish women by altering the capacity in deactivation of environmental carcinogens, even though small sample size and wide confidence interval.

The frequency of chromosomal aberrations (CAs) was evaluated in blood lymphocytes from 18 healthy subjects. Basal CA frequencies were not significantly different in GSTM1 positive and GSTM1 null subjects (P > 0.05), whereas they were considerably higher in smokers than in non-smokers. After 1 Gy dose of X-ray challenge of blood samples, CA frequencies were significantly higher in GSTM1 null subjects, compared to GSTM1 positive subjects (P < 0.005), and in smokers, compared to non-smokers. These effects are ascribed to the influence of GSTM1 genotype and of smoking status on DNA repair capacities. As the induction of CAs are associated with carcinogenesis, the challenge assay is able to detect enhanced susceptibility for CA caused by genetic predisposition of DNA repair deficiency. (C) 2002 Published by Elsevier Science B.V

Catechol-O-methyltransferase (COMT) inactivates neurotransmitters, catechol hormones and drugs such as levodopa and methyldopa. A low activity allele has been demonstrated at codon 108/158 of the soluble and membrane-bound COMT, respectively, whereby a G to A transition results in a valine to methionine substitution. Ethnic and inter-individual differences in red blood cell COMT activity have been observed in the different populations studied so far. Since, no information is available on inter-individual variability of COMT genotype in Turkish population, we genotyped 217 healthy, unrelated Turkish individuals. The allelic frequencies of COMT gene in the Turkish population were found to be the same as has been observed in Caucasians., but different from Orientals.

In the present paper, we report data on the possible genotoxic properties of two inhalation anaesthetics - sevoflurane (SVF) and isoflurane (ISF) - in peripheral blood lymphocytes of patients before, during and after anaesthesia as compared to an unexposed control group. Both anaesthetics were evaluated for genotoxic activity using the comet assay. The exposed groups consisted of 24 ASA grades 1-2 unpremedicated patients (aged 20-66 years, anaesthetized 115-162 min for elective lower abdominal surgery), while the control group consisted of 12 healthy individuals. After induction of anaesthesia (thiopenthone sodium 5-7 mg/kg, fentanyl citrate 0.1 mg and vecuronium bromid 0.1 mg/kg), anaesthesia was maintained with inhalation of SVF 1-1.5% (n = 12) or ISF 1-1.5% (n = 12) in oxygen-air mixture. Venous blood samples were obtained before the induction of anaesthesia, at 60 and 120 min of anaesthesia and on the first, third and fifth days following anaesthesia. The comet assay detects DNA damage which includes strand breaks and alkaline labile sites induced directly by genotoxic agents as well as DNA degradation due to cell death. One hundred cells from each sample were examined and graded as no tailed, short and long tailed nuclei. The mean comet response was not different between controls and patients before anaesthesia. However, similar significant increases were observed in the mean comet response in blood sampled from patients at 60 (36.5 +/- 11.2, 37.8 +/- 12.1), or 120 min (53.1 +/- 17.1, 50.0 +/- 12.2) of anaesthesia and on the first day (37.8 +/- 15.1, 35.2 +/- 15.7) after anaesthesia in SVF and ISF treated groups, respectively. Removal of the DNA damage was observed after the third day of anaesthesia and the repair was completed within 5 days. The DNA damage detected in lymphocytes of patients during anaesthesia with SVF or ISF showed similar results as demonstrated by an increased mean comet migration at 120 min of anaesthesia and the cells were able to repair the induced DNA damage completely on the fifth postoperative day. (C) 2001 Elsevier Science B.V. All rights reserved.

Investigators have demonstrated that the mutagen sensitivity assay, based on the quantification of bleomycin (BLM)-induced chromatid breaks in short-term cultured peripheral lymphocytes, can be a marker of cancer susceptibility. Although many factors can contribute to variability in human biomonitoring studies, genetic susceptibility (the influence of polymorphic metabolising genes on response to environmental mutagens) should be considered whenever appropriate. Glutathione-S-transferases (GSTs) encode a family of detoxifying phase II enzymes catalysing the conjugation of glutathione to electrophilic compounds. Studies on Caucasians indicate that about 45% of individuals lack the glutathione-S-transferase M1 (GSTM1, null) enzyme, and are therefore, theoretically at a higher risk to the toxic effects of chemicals. The aim of the present study was to investigate this hypothesis further by evaluating whether the GSTM1 genotype influences the background level of DNA damage and the induction of chromosomal aberrations by BLM in peripheral-blood lymphocytes. The alkaline comet assay was used to evaluate background levels of DNA damage in unstimulated lymphocytes while standard cytogenetic techniques were used in mitogen-stimulated lymphocytes treated with BLM. Without BLM treatment, individuals with the GSTM1 null genotype had no significant difference in frequencies of damaged cells by comparison to individuals with the GSTM1 genotype. Also, no significant differences between the two groups of individuals (GSTM1 positive and GSTM1 null) were observed for BLM-induced chromosomal aberrations. (C) 2000 Elsevier Science B.V. All rights reserved.