metabolism
No Increased Levels of the Nicotine Metabolite Cotinine in Smokers with Schizophrenia
Thu, 2013-12-26 14:59 — Feras I. QanazeThe prevalence of smoking cigarettes has repeatedly been found to be greater in schizophrenia as compared with other psychiatric patients and the general population. Patients with schizophrenia have been found to engage in heavy smoking and consumption of higher doses of nicotine, probably by deeper inhalation of cigarettes. The aim of the current study was to assess nicotine exposure through smoking by measuring urinary cotinine, the major nicotine metabolite, in a group of smokers from Greece of smokers with schizophrenia and smokers from the general population. Participants were current smokers and belonged to one of two groups: 35 patients with schizophrenia and 48 healthy controls matched in age, education, and gender. The quantitative analysis of cotinine, the major metabolite of nicotine, in urine samples was performed by a modified high performance liquid chromatography (HPLC). Patients with schizophrenia who smoke presented a significantly larger time interval between last cigarette smoked and urine sample collection, as well as a significantly higher average number of cigarettes consumed daily than normal smokers. Urinary cotinine levels of patients with schizophrenia who smoke did not significantly differ from that of normal smokers when adjusted for average number of cigarettes per day and time interval between last cigarette smoked and urine collection. These results suggest that patients with schizophrenia did not present higher nicotine exposure through smoking compared with smokers from the community. The pharmacokinetic or pharmacodynamic properties of nicotine, as well as patient medications of the patients may explain our findings.
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Lentiviral-Mediated RNAi Knockdown Yields a Novel Mouse Model for Studying Cyp2b Function
Mon, 2013-02-11 23:46 — Basma DamiriThere are few in vivo knockout models available to study the function of Cyp2 members involved in the metabolism of endogenous and exogenous chemicals. These models may help provide insight into the cytochrome P450s (CYPs) responsible for the detoxification and activation of drugs, environmental toxicants, and endobiotics. The aim of this work is to produce a potent Cyp2b-knockdown (KD) mouse for subsequent study of Cyp2b function. We made a quintuple Cyp2b-KD mouse using lentiviral-promoted short hairpin RNA (shRNA) homologous to all five murine Cyp2b subfamily members (Cyp2b9, 2b10, 2b13, 2b19, and 2b23). The Cyp2b-KD mice are viable, fertile, and without obvious gross abnormalities except for an increase in liver weight. Expression of the three hepatic Cyp2b members, 2b9, 2b10, and 2b13, is significantly repressed as demonstrated by quantitative real-time PCR and Western blotting. The constitutive androstane receptor activator, 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), was used to determine if shRNA-mediated Cyp2b10 repression could be outcompeted by Cyp2b10 induction. TCPOBOP-treated Cyp2b-KD mice show 80 -90% less Cyp2b protein expression than TCPOBOP-treated wild-type (WT) mice, demonstrating that Cyp induction does not outcompete the repressive function of the shRNA. Untreated and TCPOBOP-treated Cyp2b-KD mice are poor metabolizers of parathion compared with WT mice. Furthermore, Cyp2b-KD mice are sensitive to parathion, an organophosphate insecticide primarily metabolized by Cyp2b enzymes, when compared with WT mice. In summary, we designed an shRNA construct that repressed the expression and activity of multiple Cyp2b enzymes. We foresee that this novel Cyp2b-KD mouse model will significantly improve our understanding of the role of Cyp2b enzymes in chemical sensitivity and drug metabolism.
