Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders

Objective: The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls. Methods: The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model. Results: GSH levels were significantly reduced and, conversely, GPx activity was higher among patients than controls. GCLC_GAG-7/9 genotype (OR = 4.3, 95%CI = 1.40-14.31, p = 0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR = 6.09, 95%CI = 1.93-22.59, p = 0.003) were found to be risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or metabolic ratio. Conclusions: GCLC variants were associated with the oxidative stress profile of patients with psychotic disorders, raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.

The role of gene polymorphisms of glutamate-cysteine ligase catalytic (GCLC) enzyme against antioxidants and oxidative stress status of Individual who had contacted infectious tuberculosis

Aims: Glutamate cysteine ligase (GCL) enzyme is involved in the synthesis of glutathione, which functions as an antioxidant. Polymorphisms in the sequence of amino acids making up the gene GCLC will cause differences in enzyme expression and GCLC activity. Gene expression that is influenced by oxidative stress can be used to measure markers such as F2-isoprostanes. This study aims to examine the association between the polymorphism in the GCLC gene with glutathione plasma level and F2-isoprostanes in contacts of person with infectious tuberculosis (TB). Methodology and results: Samples are taken from the family members of pulmonary TB patients who seeks treatment at the Pulmonary Centre (Lung Health Center for Public = BBKPM) and Policlinic of Dr Wahidin Sudirohusodo Hospital, Makassar. Total of approximately 4 mL of venous blood are taken from each person with pulmonary TB contacts and furtherly analyzed using genomic PCR-RFLP method and ELISA. Our results described that contacts of person with infectious TB for approximately 6 months have polymorphism C/C genotype at 80.3%, C/T of 18.3% and T/T for 1.4% of the total 71 samples with high levels of glutathione from 0.167 to 0.548 mM/mL and F2-isoprostanes level 72.4 - 1343.9 pg/mL. Conclusion, significance and impact of study: There are no significant association between GCLC gene polymorphism with glutathione and F2-isoprostanes levels of individual who had contacted infection TB. In this study the elevation of F2-isoprostanes equal to the decrease levels of glutathione.