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Major Metabolic Pathway (major + metabolic_pathway)
Selected AbstractsIncreased glucose metabolism and ATP level in brain tissue of Huntington's disease transgenic miceFEBS JOURNAL, Issue 19 2008Judit Oláh Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by multifarious dysfunctional alterations including mitochondrial impairment. In the present study, the formation of inclusions caused by the mutation of huntingtin protein and its relationship with changes in energy metabolism and with pathological alterations were investigated both in transgenic and 3-nitropropionic acid-treated mouse models for HD. The HD and normal mice were characterized clinically; the affected brain regions were identified by immunohistochemistry and used for biochemical analysis of the ATP-producing systems in the cytosolic and the mitochondrial compartments. In both HD models, the activities of some glycolytic enzymes were somewhat higher. By contrast, the activity of glyceraldehyde-3-phosphate dehydrogenase was much lower in the affected region of the brain compared to that of the control. Paradoxically, at the system level, glucose conversion into lactate was enhanced in cytosolic extracts from the HD brain tissue, and the level of ATP was higher in the tissue itself. The paradox could be resolved by taking all the observed changes in glycolytic enzymes into account, ensuing an experiment-based detailed mathematical model of the glycolytic pathway. The mathematical modelling using the experimentally determined kinetic parameters of the individual enzymes and the well-established rate equations predicted the measured flux and concentrations in the case of the control. The same mathematical model with the experimentally determined altered Vmax values of the enzymes did account for an increase of glycolytic flux in the HD sample, although the extent of the increase was not predicted quantitatively. This suggested a somewhat altered regulation of this major metabolic pathway in HD tissue. We then used the mathematical model to develop a hypothesis for a new regulatory interaction that might account for the observed changes; in HD, glyceraldehyde-3-phosphate dehydrogenase may be in closer proximity (perhaps because of the binding of glyceraldehyde-3-phosphate dehydrogenase to huntingtin) with aldolase and engage in channelling for glyceraldehyde-3-phosphate. By contrast to most of the speculation in the literature, our results suggest that the neuronal damage in HD tissue may be associated with increased energy metabolism at the tissue level leading to modified levels of various intermediary metabolites with pathological consequences. [source] Stereoselective disposition of talinolol in manJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2002Michael Zschiesche Abstract The disposition of the ,-blocking drug talinolol is controlled by P-glycoprotein in man. Because talinolol is marketed as a racemate, we reevaluated the serum-concentration time profiles of talinolol of a previously published study with single intravenous (30 mg) and repeated oral talinolol (100 mg for 14 days) before and after comedication of rifampicin (600 mg per day for 9 days) in eight male healthy volunteers (age 22,26 years, body weight 67,84 kg) with respect to differences in the kinetic profiles of the two enantiomers S(,) talinolol and R(+) talinolol. Additionally, the metabolism of talinolol in human liver microsomes was examined. After oral administration, S(,) talinolol was slightly less absorbed and faster eliminated than R(+) talinolol. The absolute bioavailabilty of the R(+) enantiomer of talinolol was slightly but significantly higher than of its S(,) enantiomer. Coadministration of rifampicin further intensified this difference in the disposition of R(+) and S(,) talinolol (p,<,0.05). Formation of 4-trans hydroxytalinolol was the major metabolic pathway in human liver microsomes. All Clint values of S(,) were higher than of R(+) talinolol; 0.1 ,M ketoconazole inhibited the formation of all metabolites. In conclusion, the stereoselectivity of talinolol disposition is of minor importance, and most likely caused by presystemic biotransformation via CYP3A4. The less active R(+) talinolol might be suitable for phenotyping P-glycoprotein expression in man. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:303,311, 2002 [source] Permethrin resistance ratios compared by two methods of testing nymphs of the German cockroach, Blattella germanicaMEDICAL AND VETERINARY ENTOMOLOGY, Issue 2 2000H. Ladonni Summary For the German cockroach, Blattella germanica L. (Dictyoptera: Blattellidae), the permethrin resistance ratio (RR) was assessed by topical application and by tarsal contact tests, using first-instar nymphs of five strains from Tehran, Iran. Each test was replicated three or four times with 10 nymphs aged 2,3 days; mortality was scored 24 h post-treatment. The reference susceptible strain showed LD50 permethrin 0.0175 ,l/nymph from topical application, KT50 of 8.41 min and LT50 of 12.82 following tarsal contact with permethrin 15 mg/m2. In four wild strains (F1 generation) the RR varied from 4.14 to 4.7 for mortality after topical application, from 4.2 to 6.45 for mortality and 17,27 for knockdown following tarsal contact tests. Hence, overall knockdown results gave much higher RRs than for mortality data. Resistance ratios based on both methods of treatment were very similar: one strain showed a slightly higher value by topical application (RR 4.6 vs. 4.2, i.e. 1.1-fold difference) whereas the other three strains gave slightly greater RR (1.2,1.4 fold) by tarsal contact. Resistance was abolished by cotreatment with the synergist piperonyl butoxide plus permethrin (ratio 3 : 1 required for full efficacy), indicating that mixed-function oxidases were inhibited as a major metabolic pathway in all four resistant strains. [source] Cover Picture , Mol.MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 9 2009Nutr. Regular issues provide a wide range of research and review articles covering all aspects of Molecular Nutrition & Food Research. Selected topics of issue 9 are: Efficacy of isoflavones in relieving vasomotor menopausal symptoms , a systematic review. Aromatic hydroxylation is a major metabolic pathway of the mycotoxin zearalenone in vitro HOP BITTER ACIDS EFFICIENTLY BLOCK INFLAMMATION INDEPENDENT OF GR,, PPAR, OR PPAR, EGCG inhibits protein synthesis, lipogenesis and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells [source] Pharmacokinetics of riluzole: evidence for glucuronidation as a major metabolic pathway not associated with UGT1A1 genotypeBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2008H. J. M. van Kan Abstract Pharmacokinetic studies of riluzole show a large inter-individual variability of the drug's clearance and serum concentrations. Optimizing the individual dosage of riluzole may have the potential to improve the effect of riluzole treatment on survival of patients with amyotrophic lateral sclerosis (ALS). Limited data are available on the in vivo metabolic elimination of riluzole. From in vitro experiments, CYP1A2 seems to be mainly involved in riluzole clearance. However, in vitro studies suggest that formation of riluzole-glucuronide plays a role and may determine the drug's pharmacokinetic variability in patients to some extent. In the current study the formation of riluzole-glucuronide was examined in amyotrophic lateral sclerosis (ALS) patients. It also aimed at relating glucuronidation of riluzole to differential UGT1A1*28 genotypes. The formation of riluzole-glucuronide was confirmed in serum from a group of 14 ALS patients taking riluzole. Riluzole-glucuronide concentrations were positively associated with those of riluzole. In a separate group of 131 ALS patients taking riluzole, the UGT1A1*28 genotype was not associated with trough or peak serum concentrations of riluzole. This study provides evidence that the in vivo metabolic elimination of riluzole in ALS patients involves glucuronidation. The results do not indicate that glucuronidation of riluzole highly contributes to the drug's inter-individual pharmacokinetic variability. Copyright © 2007 John Wiley & Sons, Ltd. [source] Species differences in enantioselective 2-oxidations of RS-8359, a selective and reversible MAO-A inhibitor, and cinchona alkaloids by aldehyde oxidaseBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2006Kunio Itoh Abstract The 2-oxidation activity on the pyrimidine ring of RS-8359, a MAO-A inhibitor, is the major metabolic pathway catalysed by aldehyde oxidase. This study investigated the species differences in the 2-oxidation activity by using liver cytosolic fractions from rats, mice, guinea-pigs, rabbits, dogs, monkeys and humans. The Vmax/Km value for the (S)-enantiomer of RS-8359 was extremely high in monkeys and humans, moderate in guinea-pigs, and low in rats and mice. Dogs were deficient in 2-oxidation activity. The (R)-enantiomer was only oxidized at a very low rate in guinea-pigs, monkeys and humans, and not oxidized in rats, mice and rabbits. Thus, marked species differences and enantioselectivity were obvious for the 2-oxidation of the (S)-enantiomer of RS-8359. The in vitro results were in good accordance with previously reported in vivo excretion data of the 2-keto metabolite and the non-detectable plasma concentrations of the (S)-enantiomer in monkeys and humans after administration of racemic RS-8359. Enantioselectivity was also observed for the oxidation of cinchona alkaloids catalysed by aldehyde oxidase. Among the four cinchona alkaloids studied, the oxidation activity of cinchonidine, which has no substituents at the 6-hydroxy group but bears (8S,9R)-configurations, was highest. As opposed to the (S)-enantiomer, an extremely high catalytic activity of cinchonidine was confirmed in rabbits, but not in monkeys or humans. Rabbit liver aldehyde oxidase was suggested to have characteristic properties around the active site. Copyright © 2006 John Wiley & Sons, Ltd. [source] The mitochondrial proteome: A dynamic functional program in tissues and disease states,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 5 2010Robert S. Balaban Abstract The nuclear DNA transcriptional programming of the mitochondria proteome varies dramatically between tissues depending on its functional requirements. This programming generally regulates all of the proteins associated with a metabolic or biosynthetic pathway associated with a given function, essentially regulating the maximum rate of the pathway while keeping the enzymes at the same molar ratio. This may permit the same regulatory mechanisms to function at low- and high-flux capacity situations. This alteration in total protein content results in rather dramatic changes in the mitochondria proteome between tissues. A tissues mitochondria proteome also changes with disease state, in Type 1 diabetes the liver mitochondrial proteome shifts to support ATP production, urea synthesis, and fatty acid oxidation. Acute flux regulation is modulated by numerous posttranslational events that also are highly variable between tissues. The most studied posttranslational modification is protein phosphorylation, which is found all of the complexes of oxidative phosphorylation and most of the major metabolic pathways. The functional significance of these modifications is currently a major area of research along with the kinase and phosphatase regulatory network. This near ubiquitous presence of protein phosphorylations, and other posttranslational events, in the matrix suggest that not all posttranslational events have functional significance. Screening methods are being introduced to detect the active or dynamic posttranslational sites to focus attention on sites that might provide insight into regulatory mechanisms. Environ. Mol. Mutagen., 2010. Published 2010 Wiley-Liss, Inc. [source] Detailed proteome analysis of growing cells of the planctomycete Rhodopirellula baltica SH1TPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 8 2008Cao Xuan Hieu Abstract Rhodopirellula baltica SH1T, which was isolated from the water column of the Kieler Bight, a bay in the southwestern Baltic Sea, is a marine aerobic, heterotrophic representative of the ubiquitous bacterial phylum Planctomycetes. We analyzed the R. baltica proteome by applying different preanalytical protein as well as peptide separation techniques (1-D and 2-DE, HPLC separation) prior to MS. That way, we could identify a total of 1115 nonredundant proteins from the intracellular proteome and from different cell wall protein fractions. With the contribution of 709 novel proteins resulting from this study, the current comprehensive R. baltica proteomic dataset consists of 1267 unique proteins (accounting for 17.3% of the total putative protein-coding ORFs), including 261 proteins with a predicted signal peptide. The identified proteins were functionally categorized using Clusters of Orthologous Groups (COGs), and their potential cellular locations were predicted by bioinformatic tools. A unique protein family that contains several YTV domains and is rich in cysteine and proline was found to be a component of the R. baltica proteinaceous cell wall. Based on this comprehensive proteome analysis a global schema of the major metabolic pathways of growing R. baltica cells was deduced. [source] P450-catalyzed vs. electrochemical oxidation of haloperidol studied by ultra-performance liquid chromatography/electrospray ionization mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 9 2010Tove Johansson Mali'n The metabolites formed via the major metabolic pathways of haloperidol in liver microsomes, N -dealkylation and ring oxidation to the pyridinium species, were produced by electrochemical oxidation and characterized by ultra-performance liquid chromatography/electrospray ionization mass spectrometry (UPLC/ESI-MS). Liver microsomal incubations and electrochemical oxidation in the presence of potassium cyanide (KCN) resulted in two diastereomeric cyano adducts, proposed to be generated from trapping of the endocyclic iminium species of haloperidol. Electrochemical oxidation of haloperidol in the presence of KCN gave a third isomeric cyano adduct, resulting from trapping of the exocyclic iminium species of haloperidol. In the electrochemical experiments, addition of KCN almost completely blocked the formation of the major oxidation products, namely the N -dealkylated products, the pyridinium species and a putative lactam. This major shift in product formation by electrochemical oxidation was not observed for the liver microsomal incubations where the N -dealkylation and the pyridinium species were the major metabolites also in the presence of KCN. The previously not observed dihydropyridinium species of haloperidol was detected in the samples, both from electrochemical oxidation and the liver microsomal incubations, in the presence of KCN. The presence of the dihydropyridinium species and the absence of the corresponding cyano adduct lead to the speculation that an unstable cyano adduct was formed, but that cyanide was eliminated to regenerate the stable conjugated system. The formation of the exocyclic cyano adduct in the electrochemical experiments but not in the liver microsomal incubations suggests that the exocyclic iminium intermediate, obligatory in the electrochemically mediated N -dealkylation, may not be formed in the P450-catalyzed reaction. Copyright © 2010 John Wiley & Sons, Ltd. [source] | |||||||||||||