The CYP2C19*2 and CYP2C19*17 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia.

INTRODUCTION: Clozapine (CLZ) is the gold standard drug for treatment-refractory schizophrenia (TRS). However, approximately 30% of patients partially respond to CLZ, defining this subset with super refractory schizophrenia (SRS). Alterations in enzyme activity may affect CLZ responses; the CYP3A4, CYP1A2 and CYP2C19 genes are primarily responsible for CLZ metabolism. OBJECTIVE: The aim of this study was to assess if CYP2C19 variants were associated with TRS or SRS. METHODS: CYP2C19*2 loss-of-function and CYP2C19*17 gain-of-function polymorphism genotype testing were performed in 108 individuals undergoing pharmacological treatment for TRS or SRS. DNA was extracted and polymorphisms were analyzed by polymerase chain reaction (PCR) and sequencing. RESULTS: CYP2C19*17 had positive correlations with SRS and lower Brief Psychiatric Rating Scale (BPRS) scores for TRS. In addition, CYP2C19*2 was associated with lower CLZ dosages for TRS. CONCLUSION: These results show that CYP2C19*2 and CYP2C19*17 polymorphisms influence CLZ responses during schizophrenia treatment.

The hemoglobin derived peptide LVV-hemorphin-7 evokes behavioral effects mediated by oxytocin receptors.

LVV-hemorphin-7 (LVV-h7) is bioactive peptide resulting from degradation of hemoglobin ß-globin chain. LVV-h7 is a specific agonist of angiotensin IV receptor. This receptor belongs to the class of insulin-regulated aminopeptidases (IRAP), which displays oxytocinase activity. Herein, our aims were to assess whether: i) LVV-h7 modifies centrally organized behavior and cardiovascular responses to stress and ii) mechanisms underlying LVV-h7 effects involve activation of oxytocin (OT) receptors, probably as result of reduction of IRAP proteolytic activity upon OT. Adult male Wistar rats (270-370g) received (i.p.) injections of LVV-h7 (153nmol/kg), or vehicle (0.1ml). Different protocols were used: i) open field (OP) test for locomotor/exploratory activities; ii) Elevated Plus Maze (EPM) for anxiety-like behavior; iii) forced swimming test (FST) test for depression-like behavior and iv) air jet for cardiovascular reactivity to acute stress exposure. Diazepam (2mg/kg) and imipramine (15mg/kg) were used as positive control for EPM and FST, respectively. The antagonist of OT receptors (OTr), atosiban (1 and 0,1mg/kg), was used to determine the involvement of oxytocinergic paths. We found that LVV-h7: i) increased the number of entries and the time spent in open arms of the maze, an indicative of anxiolysis; ii) provoked antidepressant effect in the FS test; and iii) increased the exploration and locomotion; iv) did not change the cardiovascular reactivity and neuroendocrine responses to acute stress. Also, increases in locomotion and the antidepressant effects evoked by LVV-h7 were reverted by OTr antagonist. We conclude that LVV-h7 modulates behavior, displays antidepressant and anxiolytic effects that are mediated in part by oxytocin receptors.

Expression and immunohistochemical localization of the cytochrome P450 isoform 356A1 (CYP356A1) in oyster Crassostrea gigas.

Cytochrome P450 family (CYP) is a group of proteins virtually found in all living organisms. The main role of most CYPs is to metabolize endo and xenobiotics. Most of the studies on CYP have been carried out in mammals and other vertebrates, however recently a growing interest has been devoted to the identification of CYP isoforms in invertebrates. A gene belonging to the CYP sub-family, CYP356A1, was identified in sanitary sewage-exposed Pacific oysters, Crassostrea gigas. Through heterologous expression, we produced CYP356A1 purified protein and raised a mouse polyclonal antibody. Dot blot tests showed that oysters exposed in situ for 14 days to untreated urban effluent discharges had significantly higher levels of CYP356A1 in digestive gland. Using immunohistochemical techniques we observed that the lining epithelial cells of mantle, stomach and intestine showed a strong CYP356A1 staining, but the mucus and secretory cells were negative. Digestive diverticulum parenchyma and gills lining cells showed strong CYP356A1 reaction, while the filamentary rod (connective tissue) was negative. Free cells, as hemocytes and brown cells also showed CYP356A1 immunoreactions indicating the presence of biotransformation activity in these cells. Male germ cells at early stages expressed CYP356A1 but not sperm mature cells, suggesting that this protein could be involved in the male gonadal development. This study shows the use of a specific antibody to a mollusk CYP isoform and that this protein is inducible in oysters environmentally exposed to urban sewage effluents.