Amalia Lafuente

Human glutathione S-transferase μ (GSTμ) deficiency as a marker for the susceptibility to bladder and larynx cancer among smokers

The isoenzyme mu of glutathione S-transferase (GST mu) is dominantly inherited and the prevalence of this isoenzyme in the population is about 60%. An increased risk of lung cancer has been previously shown among smokers lacking GST mu in (Seidegard J., Pero R.W., Miller D.G., Beattie E.J. (1986) Carcinogenesis, 7, 751-753). The frequency of the phenotypes of this isoenzyme in bladder cancer patients (n = 75), in larynx cancer patients (n = 78) and healthy controls matched for age and smoking history is reported here. A significantly higher proportion of smokers in the control group had measurable GST mu compared with bladder cancer patients (54.6% vs. 33.3%, P < 0.01) and also compared to larynx cancer patients (55.1% vs. 33.3%, P < 0.01). Odds ratio analysis indicates that smokers with this polymorphic variant have an approximately 2-fold greater risk of developing these cancers.

Pro-/Anti-inflammatory Dysregulation in Patients With First Episode of Psychosis: Toward an Integrative Inflammatory Hypothesis of Schizophrenia

BACKGROUND Schizophrenia is a chronic syndrome of unknown etiology, predominantly defined by signs of psychosis. The onset of the disorder occurs typically in late adolescence or early adulthood. Efforts to study pathophysiological mechanisms in early stages of the disease are crucial in order to prompt intervention. METHODS Case-control study of first-episode psychotic (FEP) patients and matched controls. We recruited 117 patients during the first year after their FEP according to the DSM-IV criteria and recruited 106 gender-, race-, and age-matched controls between September 2010 and June 2011. RESULTS Biochemical studies carried out in peripheral mononuclear blood cells (PMBC) and plasma evidence a significant increase in intracellular components of a main proinflammatory pathway, along with a significant decrease in the anti-inflammatory ones. Multivariate logistic regression analyses identified the expression of inducible isoforms of nitric oxide synthase and cyclooxygenase in PMBC and homocysteine plasma levels as the most reliable potential risk factors and the inhibitor of the inflammatory transcription factor NFκB, IκBα, and the anti-inflammatory prostaglandin 15d-PGJ2 as potential protection factors. DISCUSSION Taken as a whole, the results of this study indicate robust phenotypical differences at the cellular machinery level in PMBC of patients with FEP. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways including the activity of nuclear receptors has interesting potential as biological markers and potential risk/protective factors for FEP. Due to its soluble nature, a notable finding in this study is that the anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis.

Effects of milk supplementation with conjugated linoleic acid (isomers cis -9, trans -11 and trans -10, cis -12) on body composition and metabolic syndrome components

The effects of conjugated linoleic acid (CLA) on body weight and body composition in man are controversial. The aim of this study was to investigate the effects of milk supplementation with CLA on body composition and on the biochemical parameters of the metabolic syndrome. This was a randomised, double-blind, placebo-controlled trial. Subjects were randomised to a daily intake of 500 ml milk supplemented with 3 g CLA (using a mixture of the bioactive isomers cis-9, trans-11 and trans-10, cis-12, marketed as Tonalin, Naturlinea; Central Lechera Asturiana) or placebo for 12 weeks. Sixty healthy men and women (aged 35-65 years) with signs of the metabolic syndrome participated (BMI 25-35 kg/m2). Dual-energy X-ray absorptiometry was used to measure body composition (week 0 baseline and week 12). Total fat mass in the CLA-milk subgroup with a BMI < or = 30 kg/m2 decreased significantly while no changes were detected in the placebo group (approximately 2 %, P = 0.01). Trunk fat mass showed a trend towards reduction (approximately 3 %, P = 0.05). CLA supplementation had no significant effect on the parameters of the metabolic syndrome, nor was it associated with changes in haematological parameters or renal function. The supplementation of milk with 3 g CLA over 12 weeks results in a significant reduction of fat mass in overweight but not in obese subjects. CLA supplementation was not associated with any adverse effects or biological changes.

Phenotype of glutathione S-transferase Mu (GSTM1) and susceptibility to malignant melanoma. MMM group. Multidisciplinary Malignant Melanoma Group.

The isoenzyme Mu of glutathione S-transferase (GSTM1) is dominantly inherited, and the prevalence of this isoenzyme in the population is about 60%. The lack of GSTM1 has been linked with cancer risk. The frequency of the phenotypes of this isoenzyme in melanoma (MM) patients (n = 197) is reported here. A significantly higher proportion of individuals in the control group (n = 147) had measurable GSTM1 than MM patients (59.1% vs 42%, P = 0.002); there was a higher proportion of positive phenotypes in general among women than among men. Odds ratio analysis indicated that individuals with this polymorphic variant have an approximately 2-fold risk of developing these cancers. GSTM1 phenotype distribution depends on age, smoking habit and tumour pathology. A group of MM patients with dysplastic naevi was also studied.

Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders

OBJECTIVE The relationship is examined of the dopamine D2 receptor (DRD2) polymorphism (TaqIA, TaqIB, -141 C Ins/Del) and the catechol-O-methyltransferase (COMT) polymorphism (A-278G, G158A) to the risk of antipsychotic-induced extrapyramidal symptoms (EPS) in schizophrenia and bipolar disorders. Participants comprised 80 cases presenting with EPS (Simpson-Angus Scale score >3) and 188 controls presenting without EPS (Simpson-Angus Scale score <or=3) participated in this study. The COMT(L) allele conferred a reduction of EPS risk of 60% to heterozygotes, but the finding did not survive correction for multiple comparisons. In the bipolar subgroup, with a COMT(L) allele protection of 70%, the reduction remained significant after Bonferroni correction. The analysis of the COMT haplotypes revealed an association of the A-G haplotype with EPS risk in the overall group and the bipolar disorder subgroup, and an association of the A-A haplotype with EPS protection in the bipolar subgroup. No significant associations were found for DRD2 or COMT A-278G polymorphisms. This is the first report of an association between the COMT polymorphism and EPS susceptibility. These results are of interest in view of the increased use of antipsychotic drugs in bipolar patients in both the acute manic and the depressive phase.

Enhanced glutathione S-transferase (GST) activity in pregnant rats treated with benzo(a)pyrene.

Administration of Benzo(a)pyrene (BP, 50 mg/kg/d) to pregnant rats significantly increased Glutathione S-transferase (GST) activity in placental tissue-extract (Vmax = 40 nmol/min/mg protein and 69 nmol/min/mg protein in controls versus treated animals respectively; P less than 0.01) and total fetal tissue-extract (Vmax = 51 nmol/min/mg protein and 82 nmol/min/mg protein in controls versus treated animals respectively; P less than 0.01) indicating an induction effect of BP on the GST system. An increase in the Km values was also observed: 1.61 x 10(-3) M and 2.84 x 10(-3) M in control versus treated placentae; 1.38 x 10(-3) M and 2.05 x 10(-3) M in control versus treated fetuses. A competitive effect on the enzyme by the BP present in the sample may also be involved. The glutathione content in both tissues did not show any changes after the treatment with BP. This increase in the GST system was not sufficient to protect the fetus. BP affected the reproductive performance of pregnant rats by significantly increasing the number of resorptions and fetal wastage, and, also, by decreasing the fetal weight.

Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics

INTRODUCTION Impaired dopamine transporter (DAT) function may be involved in antipsychotic (AP)-induced extrapyramidal symptoms (EPS). A polymorphism involving a variable number of tandem repeats (VNTR) has been described in the DAT gene (SLC6A3). OBJECTIVE We studied whether the SLC6A3 VNTR polymorphism is a risk or protection factor for AP-induced EPS. We also investigated the relationship between the polymorphism and DAT availability in the schizophrenic patients brain. METHODS Sixty-one patients receiving AP therapy participated in the EPS study. Of these, thirty-two cases presented EPS (Simpson-Angus >3) and twenty-nine without EPS (Simpson-Angus < or =3). The DAT expression was studied in fifteen AP-naive patients by [(123)I] FP-CIT SPECT. RESULTS No significant differences were observed for the more common alleles ((*)9R and (*)10R) or for genotype frequencies between patients with EPS and those without EPS. The frequency of the (*)9R and (*)10R alleles was similar to that described in other European populations. There were no significant differences in striatal DAT binding among the three major VNTR genotype groups. CONCLUSIONS Our results suggest that the VNTR polymorphism did not influence AP-induced EPS and did not affect DAT gene expression or protein function.

Immunohistochemical study of alpha, mu and pi class glutathione S transferase expression in malignant melanoma

Human pi, mu and alpha class glutathione S transferases (GST) have been localized immunohistologically in normal skin, naevi and melanoma. Pi GSTs were found principally in the stratum basalis and, to a lesser extent, in the superficial layers. Normal melanocytes showed strong nuclear and cytoplasmatic staining. Distribution of GST mu in the epidermis showed that only the stratum basale, where melanocytes are located, stained well but with weak nuclear staining. Normal melanocytes were also well stained. The alpha GSTs were relatively abundant in the upper strata and to a lesser extent, in the basal layers. The absence of nuclear staining gives these cells a target appearance. Normal melanocytes showed strong cytoplasmatic staining. The pi GSTs seem to be most persistently and strongly expressed in malignant melanoma (MM), but mu GSTs are also found, whereas the alpha GSTs were only occasionally present. The finding of the GST mu in the melanocytes of the basal layer raises new questions regarding the role of GST mu in these cells because of the inherent risk of MM in individuals with a congenital deficiency of this isoenzyme. The role of GSTs in the resistance of cells to chemotherapy is also discussed.

A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms

We present a pharmacogenetic study of acute antipsychotic (AP)-induced extrapyramidal symptoms (EPS) using an extensive linkage disequilibrium mapping approach in seven-candidate genes with a well-established link to dopamine (DRD2, DRD3, ACE, COMT, DAT, MAO-A, MAO-B). From a cohort of 321 psychiatric inpatients, 81 cases presenting with EPS (Simpson–Angus >3) and 189 controls presenting without EPS (Simpson–Angus ⩽3) took part. Eighty-four-tag single nucleotide polymorphisms (SNPs) in candidate genes were genotyped. After extensive data cleaning, 70 SNPs were analyzed for association of single markers and haplotypes. AP dosage, AP-DRD2 blockade potency and age were identified as susceptibility factors for AP-induced EPS. One SNP of the DRD3 gene, rs167771, achieved significant association with EPS risk after Bonferroni correction (nominal P-value 1.3 × 10−4) in the patients treated with risperidone (132 patients). AP-induced EPS remains a serious public health problem. Our finding of a common SNP (rs167771) in the DRD3 gene provides a strong new candidate gene for risperidone-induced EPS.

CYP2D6*3, *4, *5 AND *6 POLYMORPHISMS AND ANTIPSYCHOTIC-INDUCED EXTRAPYRAMIDAL SIDE-EFFECTS IN PATIENTS RECEIVING ANTIPSYCHOTIC THERAPY

1 The aim of the present study was to examine the relationship between CYP2D6 polymorphisms and the risk of antipsychotic (AP)‐induced extrapyramidal symptoms (EPS) in patients receiving AP treatment. The allele status for CYP2D6*3, CYP2D6*4, CYP2D6*5 and CYP2D6*6 was determined in 267 patients receiving AP therapy. Seventy‐nine cases presenting with EPS (Simpson–Angus > 3) and 188 controls without EPS (Simpson‐Angus £ 3) took part in the study. 2 We found a non‐significant over‐representation of poor metaboliser genotypes among cases, but a significant association between the mutant homozygous genotype for CYP2D6*4 (odds ratio (OR) 4.1, 95% confidence interval (CI) 1.01–16, permutated P value 0.01) and the heterozygous genotype for CYP2D6*6 (OR 5.4, 95% CI 1.13–18, permutated P value 0.003) and the risk of suffering EPS. 3 These results suggest that the CYP2D6 genotype may be a contributory factor in the development of EPS in patients undergoing AP therapy.