Cigarette smoking and heavy coffee consumption affecting response to olanzapine: The role of genetic polymorphism.

Objectives: To evaluate the effect of cigarette smoking and heavy coffee consumption on efficacy and safety of olanzapine treatment in schizophrenia patients, in relation to genetic polymorphism.Methods: The study involved 120 patients with schizophrenia, treated with olanzapine for 30 days. Therapy efficacy was determined using three different psychiatric scales, and safety by assessing metabolic adverse effects and extrapyramidal symptoms. Genotyping included CYP1A2*1C, CYP1A2*1F and CYP1A1/1A2 intergenic polymorphism, as well as CYP2D6*3, CYP2D6*4 and CYP2D6*6.Results: Cigarette smoking and heavy coffee consumption decreased the efficacy and increased the safety of olanzapine treatment (P < 0.001). Although the effect was detected only in carriers of CYP1A2*1F allele, covariate analysis revealed that it is independent of CYP1A2 genotype. Olanzapine dose was inversely correlated with the drug efficacy (P ≤ 0.002) and LDL level (P = 0.004). Women and older subjects responded better to therapy (P < 0.026), but had more certain adverse effects (P ≤ 0.049). When controlling for other relevant factors, CYP2D6 metabolizer status affects olanzapine efficacy (P = 0.032).Conclusions: We confirm the effect of cigarette smoking and heavy coffee consumption on olanzapine efficacy and safety. The relevance of CYP1A2 genotype for the described effect needs further investigation. Olanzapine treatment outcome is also affected by dose, sex, age and CYP2D6 metabolizer status.

Anxiety-like behavioural effects of extremely low-frequency electromagnetic field in rats.

In recent years, extremely low-frequency electromagnetic field (ELF-EMF) has received considerable attention for its potential biological effects. Numerous studies have shown the role of ELF-EMF in behaviour modulation. The aim of this study was to investigate the effect of short-term ELF-EMF (50 Hz) in the development of anxiety-like behaviour in rats through change hypothalamic oxidative stress and NO. Ten adult male rats (Wistar albino) were divided in two groups: control group-without exposure to ELF-EMF and experimental group-exposed to ELF-EMF during 7 days. After the exposure, time open field test and elevated plus maze were used to evaluate the anxiety-like behaviour of rats. Upon completion of the behavioural tests, concentrations of superoxide anion (O2·-), nitrite (NO2-, as an indicator of NO) and peroxynitrite (ONOO-) were determined in the hypothalamus of the animals. Obtained results show that ELF-EMF both induces anxiety-like behaviour and increases concentrations of O2·- and NO, whereas it did not effect on ONOO- concentration in hypothalamus of rats. In conclusion, the development of anxiety-like behaviour is mediated by oxidative stress and increased NO concentration in hypothalamus of rats exposed to ELF-EMF during 7 days.

Lipid peroxidative damage on Cisplatin exposure and alterations in antioxidant defense system in rat kidneys: a possible protective effect of selenium.

Cisplatin (Cis-diamminedichloroplatinum II, CP) is an important chemotherapeutic agent, useful in the treatment of several cancers, but with several side effects such as nephrotoxicity. The present study investigated the possible protective effect of selenium (Se) against CP-induced oxidative stress in the rat kidneys. Male Wistar albino rats were injected with a single dose of cisplatin (7 mg CP/kg b.m., i.p.) and selenium (6 mg Se/kg b.m, as Na(2)SeO(3), i.p.), alone or in combination. The obtained results showed that CP increased lipid peroxidation (LPO) and decreased reduced glutathione (GSH) concentrations, suggesting the CP-induced oxidative stress, while Se treatment reversed this change to control values. Acute intoxication of rats with CP was followed by statistically significant decreased activity of antioxidant defense enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and glutathione-S-transferase (GST). Treatment with Se reversed CP-induced alterations of antioxidant defense enzyme activities and significantly prevented the CP-induced kidney damage.

Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2 -163C>A polymorphism.

OBJECTIVES: To investigate the association of CYP1A2 genetic polymorphisms with the inducing effect of heavy coffee consumption on CYP1A2 activity in Serbian and Swedish populations, and to determine the frequency of the CYP1A2 genetic polymorphisms in Serbs. METHODS: Using PCR-RFLP and the tag-array minisequencing method, 126 Serbian healthy volunteers were genotyped for -3860G>A, -2467delT, -739T>G, -729C>T, -163C>A, 2159G>A, and 4795G>A. For 64 nonsmoking participants, the data on CYP1A2 activity (plasma paraxanthine/caffeine ratio) and coffee consumption habit were available from our previous study. The data on CYP1A2 genotype, enzyme activity, and coffee consumption from 114 Swedish healthy nonsmoking subjects were included in the analyses. RESULTS: In Serbs, CYP1A2 polymorphisms -3860G>A, -2467delT, -739T>G, -729C>T, -163C>A, and 2159G>A were found at the frequencies of 0.4, 5.0, 3.4, 0.7, 61.1, and 56.0%, respectively, while 4795G>A was not detected. Significant association of heavy coffee consumption with high CYP1A2 enzyme activity was observed only in carriers of -163 A/A. Increasing effect of -163C>A on CYP1A2 inducibility was found in both Serbian (P=0.022) and Swedish (P=0.016) nonsmoking heavy coffee consumers. There was no significant difference in CYP1A2 enzyme activity among genotypes in non-heavy coffee consumers. The results indicate that 22 and 14% of the phenotypic variability among Serbian and Swedish heavy coffee consumers, respectively, might be explained by -163C>A polymorphism. CONCLUSIONS: CYP1A2 polymorphism -163C>A has an important increasing effect on CYP1A2 inducibility by heavy coffee consumption and may possibly be a contributing factor for interindividual variations in CYP1A2 enzyme activity.

Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes.

OBJECTIVES: To investigate the influence of coffee consumption on CYP1A2 enzyme activity controlling for the effects of smoking and oral contraceptive (OC) use among Serbs and Swedes and to compare CYP1A2 activity between the two populations. METHODS: Data on oral contraceptive use, habitual coffee consumption and smoking habits were obtained from 100 Serbian and 149 Swedish healthy volunteers using a detailed questionnaire. CYP1A2 activity was estimated by plasma paraxanthine/caffeine (17X/137X) ratio analysed by reversed-phase HPLC after oral administration of 100 mg caffeine. RESULTS: Daily consumption of at least three cups of coffee significantly increased CYP1A2 enzyme activity in both Serbs (P=0.0002) and Swedes (P<0.0001). Among non-smokers and non-OC users, heavy coffee consumption significantly increased CYP1A2 activity in Serbs (mean difference 0.11; 95% CI of the mean difference 0.04, 0.18; P=0.003) and Swedes (mean difference 0.07; 95% CI of the mean difference 0.01, 0.12; P=0.02). Significantly higher 17X/137X ratio was detected in Serbian smokers compared to non-smokers. There was no significant gender difference in CYP1A2 activity in Serbs. Controlling for the effect of smoking, heavy coffee consumption habit and oral contraceptive use, significantly lower 17X/137X ratio was observed in Serbs than in Swedes (P=0.0003). CONCLUSIONS: Habitual heavy coffee consumption increases CYP1A2 activity. Polycyclic aromatic hydrocarbons formed during roasting of coffee beans might partly be responsible for this effect. The reason for the observed lower CYP1A2 activity in Serbs as compared to Swedes remains to be investigated.