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Comparative Study 2013; 34(Suppl 2): 55-63 PubMed PMID: 24362093 Citation  Keywords:  Animals, Benzo(a)pyrene:metabolism, Carcinogens:metabolism, Cytochrome P-450 CYP1A1:metabolism, Cytochromes b5:pharmacology, Humans, Inactivation, Metabolic, Male, Microsomes, Liver:drug effects, Oxidation-Reduction, Rats,.   

OBJECTIVES: Cytochrome P450 (CYP) 1A1 is the most important enzyme in both activation and detoxification of carcinogenic benzo[a]pyrene (BaP), in combination with microsomal epoxide hydrolase (mEH). To evaluate metabolism of BaP in human, identification of a suitable animal model that mimics the metabolic fate of BaP in human is of great importance. The aim of this work was to compare BaP oxidation by human CYP1A1 and CYP1A1 of one animal model, rat. Investigation of the effect of cytochrome b5 on BaP oxidation by CYP1A1 was another target of this study.

METHODS: High performance liquid chromatography (HPLC) was employed for separation of BaP metabolites formed by enzymatic systems. Their structures were identified by mass- and NMR-spectrometry.

RESULTS: Human hepatic microsomes oxidized BaP to BaP-9,10-dihydrodiol, BaP-4,5-dihydrodiol, BaP-7,8-dihydrodiol, BaP-1,6-dione, BaP-3,6-dione and BaP-3-ol. The same metabolites were generated by rat liver microsomes, but BaP-9-ol and a metabolite Mx, the structure of which has not been identified as yet, were also formed in these microsomes. Human CYP1A1 expressed with NADPH:CYP reductase (POR) in Supersomes™ oxidized BaP to the same metabolites as microsomes, but BaP-4,5-dihydrodiol has not been detected. Rat recombinant CYP1A1 in this SupersomesTM system oxidized BaP to BaP-9,10-dihydrodiol, a metabolite Mx, BaP-4,5-dihydrodiol, BaP-7,8-dihydrodiol, BaP-1,6-dione, BaP-3,6-dione, BaP-9-ol and BaP-3-ol. Addition of cytochrome b5 to rat and human recombinant CYP1A1 systems led to a more than 2-fold increase in BaP oxidation.

CONCLUSION: The results show similarities between human and rat CYP1A1 in BaP oxidation and demonstrate rats as a suitable model mimicking BaP oxidation in human....

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Journal Article 2012; 33(Suppl 3): 72-76 PubMed PMID: 23353847 Citation  Keywords:  Animals, Anti-Inflammatory Agents, Non-Steroidal:toxicity, Aspirin:toxicity, Dose-Response Relationship, Drug, Embryo, Nonmammalian:drug effects, Inactivation, Metabolic:physiology, Lethal Dose 50, Oxidative Stress:drug effects, Toxicity Tests, Acute, Wat.   

OBJECTIVES: The aim of this study was to compare the acute toxicity of acetylsalicylic acid to embryonic and juvenile stages of aquarium fish - zebrafish (Danio rerio), oxidative stress parameters and detoxifying enzyme.

METHODS: Tests were performed according to OECD No. 203 (Fish, acute toxicity test) and OECD No. 212 (Fish, short-term toxicity test on embryo and sac-fry stages) methodology.

RESULTS: The results showed the mean acetylsalicylic acid LC50 value to be 567.7 mg/L in juvenile zebrafish. The acute toxicity of acetylsalicylic acid for zebrafish embryos was 274.6 mg/L. Statistically significantly higher activity of GST was found in concentrations 340, 380 and 420 mg/L of acetylsalicylic acid. TBARS, GPx and GST didn't show statistically significant activity in tested concentrations of acetylsalicylic acid.

CONCLUSIONS: The results revealed a statistically significantly higher degree of sensitivity in the embryonic stages of zebrafish compared to its juveniles. Acetylsalicylic acid did not cause statistically significantly higher antioxidative defence in zebrafish....

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Journal Article 2012; 33(Suppl 2): 43-49 PubMed PMID: 23183509 Citation  Keywords:  Animals, Animals, Congenic, Chromosomes, Mammalian, Disease Models, Animal, Glucose Intolerance:drug therapy, Hypertension:drug therapy, Lipids:blood, Male, Metabolic Syndrome X:drug therapy, Ondansetron:pharmacology, Polydactyly:genetics, Rats, Rats, Inb.   

OBJECTIVES: Ondansetron is an antagonist of 5-HT3 receptors mostly used as an antiemetic yet known to modulate metabolism and appetite. We tested the metabolic effects of ondansetron in newly derived congenic rat strain, carrying limited chromosome 8 regions of (PD) Brown Norway (BN) and polydactylous (PD) strain origins (including variant serotonin receptor Htr3b gene) within the genomic background of highly inbred model of metabolic syndrome, the spontaneously hypertensive rat (SHR).

METHODS: Adult, standard diet-fed male rats of SHR and the congenic SHR.(PD/BN)8 strains received ondansetron (2mg/kg body weight/day) or vehicle (n=6/strain/treatment) via oral gavage for 14 days while we followed their metabolic and morphometric profiles including glucose tolerance and triacylgycerol and cholesterol concentrations in 20 lipoprotein fractions.

RESULTS: We fine-mapped the chromosome 8 differential segment in the new SHR.(PD/BN)8 congenic strain: it comprises BN-derived region together with an adjacent 422kb stretch of PD origin. The SHR.(PD/BN)8 rats were heavier than SHR, the fasting glucose was significantly higher in ondansetron-treated congenic than in SHR (post-hoc Tukey's HSD p=0.02). Compared to SHR, ondansetron induced significantly more robust increases of cholesterol and triacylglycerol concentrations in total, chylomicron, VLDL and HDL particles in the SHR.(PD/BN)8 congenic strain.

CONCLUSION: We established new congenic model with distinct pharmacogenetic profile related to metabolic effects of ondansetron, facilitating thus the search for responsible genetic variants within the limited genomic region demarcated by the differential segment....

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Journal Article 2012; 33(1): 11-15 PubMed PMID: 22467105 Citation  Keywords:  Adipocytes:metabolism, Adipokines, Adipose Tissue:metabolism, Humans, Metabolic Diseases, Obesity:metabolism,.   

: Adipose tissue is an endocrine and paracrine organ that releases a large number of bioactive mediators. Approximately 100 adipokines have been identified including cytokines, chemokines, growth factors and enzymes. The use of adipoproteomic analyses resulted in new findings and, in consequence, the number of new adipokines is rising rapidly. Novel adipokines such as visfatin, vaspin and omentin were discovered about five years ago. Visfatin and vaspin production and secretion take place in adipocytes, but omentin comes from the stromal cells of adipose tissue. Several differences are noticeable between these adipokines especially in correlation with obesity as visfatin and vaspin serum levels increase in obese subjects while omentin serum levels decrease. It has been suggested that these adipokines act as insulin-sensitizers/insulin-mimetics. Increasing number of publications reporting the role of new adipokines does not allow to assess clearly the influence of those adipokines on the pathogenesis of obesity....

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Journal Article 2011; 32(Suppl 2): 55-59 PubMed PMID: 22101884 Citation  Keywords:  Adiposity:physiology, Adolescent, Anthropometry, Atherosclerosis:epidemiology, Body Mass Index, Body Weight:physiology, Cardiovascular Diseases:epidemiology, Child, Energy Intake, Female, Humans, Life Style, Lipids:blood, Male, Metabolic Diseases:epidemio.   

OBJECTIVES: Obesity is associated with increased inflammation which represents a link to atherosclerosis and cardiovascular disease. Lipoprotein associated phospholipase A2 (Lp-PLA2) is an independent marker of inflammation and atherosclerosis risk. To assess the impact of weight loss on metabolic markers of atherosclerosis including Lp-PLA2 we examined a group of Czech non-diabetic obese/overweight children exposed to a lifestyle intervention.

PATIENTS AND METHODS: Fourty unrelated overweight/obese non-diabetic Czech children (13.7 ± 2.1 years, average BMI at baseline 29.8 ± 2.6 kg/m2) underwent 4 weeks of lifestyle modification (reduction of energy intake to age matched optimum and supervised physical activity). Anthropometrical and biochemical variables were determined at baseline and after the intervention. Lp-PLA2 mass concentration was assessed using the ELISA kit. Wilcocson's rank test and Spearman's correlation were used for statistical analysis.

RESULTS: A significant decrease of BMI and waist circumference was associated with significant changes of plasma lipoprotein and glycaemia levels. Mass concentration of Lp-PLA2 at the baseline was 402 ± 94 μg/ml, after the intervention 368 ± 105 μg/ml (p=0.008). Change in Lp-PLA2 was associated with triglyceride level decrease (p=0.009).

CONCLUSION: Intensive lifestyle modification leading to body weight decrease results in significant changes of plasma lipoprotein levels and, also, a drop of Lp-PLA2 levels in paediatric obese patients. However, even after the intervention Lp-PLA2 concentrations in this patient group remain elevated suggesting possible increased atherosclerosis risk in later life....

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Journal Article 2011; 32(Suppl 2): 32-36 PubMed PMID: 22101880 Citation  Keywords:  Adiposity:genetics, Adult, Aged, Body Composition:physiology, Body Mass Index, Energy Intake, Exercise, Female, Genetic Variation:genetics, Genotype, Heterozygote, Humans, Insulin Resistance:genetics, Life Style, Metabolic Clearance Rate:physiology, Middl.   

OBJECTIVES: The AHSG (alpha2 Heremans-Schmid glycoprotein) gene is suggested to be important for the regulation of body fat and insulin sensitivity. Our study aimed to investigate the relationship between the common Thr248Met (rs4917) variant and obesity characteristics after an intervention with overweight females.

MATERIAL AND METHODS: We analyzed 105 unrelated overweight/obese nondiabetic Czech adult females (49.0 ± 12.1 years, BMI over 28.6 kg/m2, mean BMI before intervention 32.8 ± 4.1 kg/m2) before and after 10 weeks of lifestyle modification. Biochemical and anthropometrical measurements were performed. The life style modification program consisted of a reduction of energy intake to an age-adjusted optimum and an exercise program (four units per week). The mean weight loss was 3.2 ± 3.5 kg (3.7 ± 4.0%).

RESULTS: Thr/Thr homozygotes (N=52) increased lean muscle mass (p<0.05), decreased total body fat (kg) (p<0.005) and increased basal metabolic rate (BMR) per 1 kg body weight (p<0.005) in comparison with the Met carriers (N=52), but an association between BMI decrease and AHSG variants was not found.

CONCLUSION: AHSG gene variants modify the effect of physical activity on BMR. Carriers of the Thr248Thr genotype showed a higher benefit from the lifestyle intervention (expressed as changes in body fat, active muscle and basal metabolic rate)....

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Journal Article 2010; 31(4): 497-506 PubMed PMID: 20802460 Citation  Keywords:  Adiponectin:blood, Adult, Female, Genotype, Humans, Insulin Resistance:genetics, Logistic Models, Metabolic Syndrome X:etiology, Middle Aged, Obesity:genetics, Odds Ratio, Overweight:genetics, Poland, Polymorphism, Genetic, Resistin:blood,.   

OBJECTIVE: Obesity may be accompanied by enhanced metabolic disturbances but not all obese patients suffer from metabolic syndrome. Since metabolic homeostasis is under control of genetic factors underlying expression of adipokines, we aimed to compare the serum concentrations of adiponectin and resistin, and polymorphism in their genes, in overweight or obese Polish women.

MATERIAL AND METHODS: The study included 265 women with BMI above 25 kg/m2 (140 metabolically healthy and 125 with metabolic syndrome) and 104 non-obese women as a control group. Anthropometric parameters (BMI, BIA, WHR), blood pressure, lipid, glucose and HOMA-IR profiles as well as serum concentrations of adiponectin, HMW adiponectin and resistin were evaluated. Gene polymorphisms of adiponectin gene (276G/T; 11377C/G; 11391G/A) and resistin gene (420C/G; 62G/A; 537A/C) were analyzed using TaqMan SNP genotyping assays.

RESULTS: Higher serum concentrations of total adiponectin and lower levels of resistin were found in metabolically healthy patients when compared to those diagnosed with metabolic syndrome. No differences of serum HMW and resistin concentrations were observed between overweight or obese but metabolically healthy subjects and normal weight controls. No associations of investigated polymorphisms and the presence of metabolic syndrome were noticed in overweight/obese women with metabolic syndrome.

CONCLUSIONS: The assessment of total adiponectin in sera seems to be promising target in distinguishing subjects with obesity who undergo a diagnostic procedure for metabolic syndrome. Moreover, the evaluation of adipokine array may help to select patients with higher risk of metabolic disturbances that are associated with severe diseases....

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Journal Article 2010; 31(1): 11-18 PubMed PMID: 20150871 Citation  Keywords:  Cannabinoid Receptor Modulators:biosynthesis, Catechol O-Methyltransferase:genetics, Cytochrome P-450 CYP2D6:genetics, Enzymes:genetics, Genetic Predisposition to Disease, Health, Humans, Mental Disorders:genetics, Metabolic Networks and Pathways:genetics.   

: Endogenous morphine has been detected in human tissues from the vascular, immune and nervous systems. The genes/enzymes (CYP2D6, COMT and PNMT) that are involved in the biosynthesis of morphine have variations that affect their functionality. Some of these variations are the result of single nucleotide polymorphisms of DNA sequences. This review highlights some of the functional differences in the critical enzymes required for the biosynthesis of morphine that may affect human health. These variations have been shown to change the way animals react to stressors, perceive pain and behave. The presence of morphine signaling in almost all organ systems suggests that it is most likely playing a role in maintaining the health and promoting the normal functioning of these physiological systems....

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