RESUMEN
IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.
Asunto(s)
Glioma/metabolismo , Ácido Glutámico/biosíntesis , Transaminasas/fisiología , Línea Celular Tumoral , Glioma/fisiopatología , Ácido Glutámico/efectos de los fármacos , Glutaratos/metabolismo , Glutaratos/farmacología , Homeostasis/efectos de los fármacos , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/fisiología , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/fisiología , Mutación , Oxidación-Reducción/efectos de los fármacos , Proteínas Gestacionales/genética , Proteínas Gestacionales/fisiología , Transaminasas/antagonistas & inhibidores , Transaminasas/genéticaRESUMEN
BACKGROUND: 7,8-Diaminopelargonic acid synthase (BioA), an enzyme of biotin biosynthesis pathway, is a well-known promising target for anti-tubercular drug development. METHODS: In this study, structure-based virtual screening was employed against the active site of BioA to identify new chemical entities for BioA inhibition and top ranking compounds were evaluated for their ability to inhibit BioA enzymatic activity. RESULTS: Seven compounds inhibited BioA enzymatic activity by greater than 60% at 100 µg/mL with most potent compounds being A36, A35 and A65, displaying IC50 values of 10.48 µg/mL (28.94 µM), 33.36 µg/mL (88.16 µM) and 39.17 µg/mL (114.42 µM), respectively. Compounds A65 and A35 inhibited Mycobacterium tuberculosis (M. tuberculosis) growth with MIC90 of 20 µg/mL and 80 µg/mL, respectively, whereas compound A36 exhibited relatively weak inhibition of M. tuberculosis growth (83% inhibition at 200 µg/mL). Compound A65 emerged as the most potent compound identified in our study that inhibited BioA enzymatic activity and growth of the pathogen and possessed drug-like properties. CONCLUSION: Our study has identified a few hit molecules against M. tuberculosis BioA that can act as potential candidates for further development of potent anti-tubercular therapeutic agents.
Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Transaminasas/antagonistas & inhibidores , Antituberculosos/síntesis química , Antituberculosos/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Clonación Molecular , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Perfilación de la Expresión Génica , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/crecimiento & desarrollo , Relación Estructura-Actividad , Transaminasas/genética , Transaminasas/metabolismoRESUMEN
One of the worldwide metabolic health dilemma is nonalcoholic fatty liver diseases (NAFLD). Researchers are searching effective drug to manage NAFLD patients. One of the best way to manage the metabolic imperfection is through natural principal isolated from different sources. Butein, a natural compound known to have numerous pharmacological application. In the current study we assessed the therapeutic effect of butein administration on liver function tests, oxidative stress, antioxidants, lipid abnormalities, serum inflammatory cytokines, and mitochondrial reactive oxygen species levels, in rats with methionine-choline deficient (MCD) diet induced NAFLD. Male Wistar rats were treated with MCD diet with/without butein (200 mg/kg body wt. orally) for 6 weeks. The protective effect of butein, were evident from decreased transaminase activities, restoration of albumin, globulin, albumin/globulin ratio, and oxidants in serum (P < 0.01), further it improved liver antioxidant status (P < 0.01). Butein significantly lowered lipid profile parameters (P < 0.01), suppressed inflammatory cytokines (P < 0.01), and improved liver histology. Further to understand the possible mechanism behind the hepatoprotective and lipid lowering effect of butein, the activities of heme oxygenase (HO1), myeloperoxidase (MPO), and mitochondrial reactive oxygen species (ROS) were measured. We found that butein supplementation significantly decreased the activity of HO1 (P < 0.001), and increased the activity of MPO (P < 0.001). Furthermore butein attenuated mitochondrial ROS produced in NAFLD condition. Present study shows that butein supplementation restore liver function by altering liver oxidative stress, inflammatory markers, vital defensive enzyme activities, and mitochondrial ROS. In summary, butein has remarkable potential to develop effective hepato-protective drug. © 2018 BioFactors, 44(3):289-298, 2018.
Asunto(s)
Chalconas/farmacología , Deficiencia de Colina/tratamiento farmacológico , Dieta/efectos adversos , Hipolipemiantes/farmacología , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Administración Oral , Albúminas/metabolismo , Animales , Colina/metabolismo , Deficiencia de Colina/etiología , Deficiencia de Colina/metabolismo , Deficiencia de Colina/patología , Globulinas/metabolismo , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Metionina/deficiencia , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Peroxidasa/antagonistas & inhibidores , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Transaminasas/antagonistas & inhibidores , Transaminasas/metabolismoRESUMEN
Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors; however, the function of BCATs in macrophages is unknown. Here we show that BCAT1 is the predominant BCAT isoform in human primary macrophages. We identify ERG240 as a leucine analogue that blocks BCAT1 activity. Selective inhibition of BCAT1 activity results in decreased oxygen consumption and glycolysis. This decrease is associated with reduced IRG1 levels and itaconate synthesis, suggesting involvement of BCAA catabolism through the IRG1/itaconate axis within the tricarboxylic acid cycle in activated macrophages. ERG240 suppresses production of IRG1 and itaconate in mice and contributes to a less proinflammatory transcriptome signature. Oral administration of ERG240 reduces the severity of collagen-induced arthritis in mice and crescentic glomerulonephritis in rats, in part by decreasing macrophage infiltration. These results establish a regulatory role for BCAT1 in macrophage function with therapeutic implications for inflammatory conditions.
Asunto(s)
Ciclo del Ácido Cítrico , Leucina/análogos & derivados , Leucina/farmacología , Macrófagos Peritoneales/metabolismo , Transaminasas/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Glomerulonefritis/tratamiento farmacológico , Humanos , Hidroliasas/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratas , Succinatos/metabolismo , Transaminasas/antagonistas & inhibidoresRESUMEN
KEY POINTS: Using recombinant DNA technology, the present study provides the first strong and direct evidence indicating that ß-alanine is an efficient substrate for the mammalian transaminating enzymes 4-aminobutyrate-2-oxoglutarate transaminase and alanine-glyoxylate transaminase. The concentration of carnosine and anserine in murine skeletal and heart muscle depends on circulating availability of ß-alanine, which is in turn controlled by degradation of ß-alanine in liver and kidney. Chronic oral ß-alanine supplementation is a popular ergogenic strategy in sports because it can increase the intracellular carnosine concentration and subsequently improve the performance of high-intensity exercises. The present study can partly explain why the ß-alanine supplementation protocol is so inefficient, by demonstrating that exogenous ß-alanine can be effectively routed toward oxidation. ABSTRACT: The metabolic fate of orally ingested ß-alanine is largely unknown. Chronic ß-alanine supplementation is becoming increasingly popular for improving high-intensity exercise performance because it is the rate-limiting precursor of the dipeptide carnosine (ß-alanyl-l-histidine) in muscle. However, only a small fraction (3-6%) of the ingested ß-alanine is used for carnosine synthesis. Thus, the present study aimed to investigate the putative contribution of two ß-alanine transamination enzymes, namely 4-aminobutyrate-2-oxoglutarate transaminase (GABA-T) and alanine-glyoxylate transaminase (AGXT2), to the homeostasis of carnosine and its methylated analogue anserine. We found that, when transfected into HEK293T cells, recombinant mouse and human GABA-T and AGXT2 are able to transaminate ß-alanine efficiently. The reaction catalysed by GABA-T is inhibited by vigabatrin, whereas both GABA-T and AGXT2 activity is inhibited by aminooxyacetic acid (AOA). Both GABA-T and AGXT2 are highly expressed in the mouse liver and kidney and the administration of the inhibitors effectively reduced their enzyme activity in liver (GABA-T for vigabatrin; GABA-T and AGXT2 for AOA). In vivo, injection of AOA in C57BL/6 mice placed on ß-alanine (0.1% w/v in drinking water) for 2 weeks lead to a 3-fold increase in circulating ß-alanine levels and to significantly higher levels of carnosine and anserine in skeletal muscle and heart. By contrast, specific inhibition of GABA-T by vigabatrin did not affect carnosine and anserine levels in either tissue. Collectively, these data demonstrate that homeostasis of carnosine and anserine in mammalian skeletal muscle and heart is controlled by circulating ß-alanine levels, which are suppressed by hepatic and renal ß-alanine transamination upon oral ß-alanine intake.
Asunto(s)
Anserina/metabolismo , Carnosina/metabolismo , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Transaminasas/metabolismo , beta-Alanina/metabolismo , Ácido Aminooxiacético/farmacología , Animales , Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , GABAérgicos/farmacología , Células HEK293 , Homeostasis , Humanos , Riñón/metabolismo , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Transaminasas/antagonistas & inhibidores , Transaminasas/genética , Vigabatrin/farmacología , beta-Alanina/sangre , beta-Alanina/orinaRESUMEN
Kynurenine aminotransferases convert kynurenine to kynurenic acid and play an important role in the tryptophan degradation pathway. Kynurenic acid levels in brain have been hypothesized to be linked to a number of central nervous system (CNS) disorders. Kynurenine aminotransferase II (KATII) has proven to be a key modulator of kynurenic acid levels in brain and, thus, is an attractive target to treat CNS diseases. A sensitive, high-throughput, label-free RapidFire mass spectrometry assay has been developed for human KATII. Unlike other assays, this method is directly applicable to KATII enzymes from different animal species, which allows us to select proper animal model(s) to evaluate human KATII inhibitors. We also established a coupled fluorescence assay for human KATII. The short assay time and kinetic capability of the fluorescence assay provide a useful tool for orthogonal inhibitor validation and mechanistic studies.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Pruebas de Enzimas/métodos , Inhibidores Enzimáticos/farmacología , Transaminasas/antagonistas & inhibidores , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/enzimología , Inhibidores Enzimáticos/química , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Ácido Quinurénico/metabolismo , Espectrometría de Masas/métodos , Espectrometría de Fluorescencia/métodos , Transaminasas/metabolismoRESUMEN
BioA, a pyridoxal 5'-phosphate (PLP) dependent aminotransferase, catalyzes the second step of biotin biosynthesis, converting 7-keto-8-aminopelargonic acid (KAPA) into 7,8-diaminopelargonic acid (DAPA). Amiclenomycin (ACM) isolated from cultures of different Streptomyces strains is a potent mechanism-based inhibitor of BioA that operates via an aromatization mechanism, irreversibly labeling the PLP cofactor. However, ACM is plagued by inherent chemical stability. Herein we describe the synthesis of four inhibitors, inspired by ACM but containing an allylic amine as the chemical warhead, designed to both improve stability and operate via a complementary Michael addition-pathway upon enzymatic oxidation of the allylic amine substrate to an enimine. Acyclic analogue M-1 contains a terminal olefin as the pro-Michael acceptor. The synthesis of M-1 features an alkyne-zipper reaction and the Overman rearrangement as key synthetic operations. The cyclic analogues M-2/3/4 contain either an endocyclic or exocyclic olefin as the pro-Michael acceptor. These were all prepared using a common strategy employing DIBAL reduction of a precursor bicyclic lactam, followed by in situ Horner-Wadsworth-Emmons (HWE) olefination as the key synthetic steps.
Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Transaminasas/antagonistas & inhibidores , Aminobutiratos/síntesis química , Aminobutiratos/química , Aminobutiratos/farmacología , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Biocatálisis , Biotina/biosíntesis , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , Mycobacterium tuberculosis/enzimología , Streptomyces/química , Relación Estructura-Actividad , Transaminasas/química , Transaminasas/metabolismoRESUMEN
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
Asunto(s)
Benzofuranos/síntesis química , Benzofuranos/uso terapéutico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Sulfonamidas/síntesis química , Sulfonamidas/uso terapéutico , Transaminasas/antagonistas & inhibidores , Animales , Benzofuranos/química , Calcio/antagonistas & inhibidores , Calcio/metabolismo , Células Cultivadas , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Ácido Glutámico/efectos de los fármacos , Ácido Glutámico/metabolismo , Humanos , Técnicas In Vitro , Modelos Moleculares , Estructura Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Ratas , Ratas Endogámicas Lew , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The anti-oxidant activities of fucosterol isolated from the marine algae Pelvetia siliquosa were investigated. Fucosterol exhibited a significant decrease in serum transaminase activities elevated by hepatic damage induced by CCl4-intoxication in rats. Fucosterol inhibited the sGOT and sGPT activities by 25.57 and 63.16%, respectively. Fucosterol showed the increase in the anti-oxidant enzymes such as hepatic cytosolic superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-px) activities by 33.89, 21.56 and 39.24%, respectively, in CCl4-intoxicated rats. These results suggest that fucosterol possess not only the anti-oxidant, but also the hepatoprotective activities in rats.
Asunto(s)
Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Eucariontes/química , Estigmasterol/aislamiento & purificación , Estigmasterol/farmacología , Administración Oral , Animales , Antioxidantes/química , Tetracloruro de Carbono/administración & dosificación , Tetracloruro de Carbono/efectos adversos , Intoxicación por Tetracloruro de Carbono/diagnóstico , Catalasa/biosíntesis , Catalasa/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Pruebas Enzimáticas Clínicas , Esquema de Medicación , Glutatión Peroxidasa/biosíntesis , Glutatión Peroxidasa/farmacología , Hexanos , Inyecciones Intraperitoneales , Corea (Geográfico) , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacocinética , Premedicación , Ratas , Ratas Sprague-Dawley , Silimarina/administración & dosificación , Silimarina/farmacocinética , Estigmasterol/análogos & derivados , Estigmasterol/química , Superóxido Dismutasa/biosíntesis , Superóxido Dismutasa/farmacología , Transaminasas/antagonistas & inhibidores , Transaminasas/biosíntesis , Transaminasas/efectos de los fármacosRESUMEN
Catabolism of L-methionine by Escherichia coli strain B SPAO led to the formation of ethylene as a secondary metabolite (ethylenogenesis). Methionine was initially deaminated by a transamination reaction to the 2-oxo acid 2-oxo-4-methylthiobutyric acid (KMBA) which was then converted to ethylene. The utilization of L-methionine as an additional nitrogen source was investigated by examining ethylene synthesis under different nitrogen supply conditions. Ethylene formation in batch culture was unaffected by the concentration of the precursor L-methionine in the medium although increasing concentrations of NH4Cl resulted in progressively less ethylene formation. Cultures grown without L-methionine did not produce ethylene but were able to synthesize ethylene when L-methionine or KMBA was provided. Addition of L-tyrosine to batch cultures reduced the yield of ethylene after 42 h by 54%. Under these conditions the maximum transient level of KMBA was reduced by 32% and occurred later compared to when L-methionine was the only amino acid supplement. Continuous cultures grown under ammonia limitation produced both ethylene and KMBA. In contrast, when glucose was limiting, neither of these metabolites were produced. Cells harvested from continuous cultures grown under glucose or ammonia limitation were able to synthesize ethylene from either L-methionine or KMBA although their capacity for ethylene synthesis (ethylenogenic capacity) was optimal under ammonia limitation (C:N ratio = 20).
Asunto(s)
Escherichia coli/metabolismo , Etilenos/biosíntesis , Metionina/metabolismo , Cloruro de Amonio/farmacología , Proteínas Bacterianas/metabolismo , Butiratos/metabolismo , Desaminación , Retroalimentación , Glucosa/metabolismo , Metionina/farmacología , Nitrógeno/metabolismo , Compuestos de Sulfhidrilo , Transaminasas/antagonistas & inhibidores , Transaminasas/metabolismo , Tirosina/farmacologíaRESUMEN
A large number of structurally diverse di- and tripeptides containing the alanine racemase inactivator beta-chloro-L-alanine (beta-Cl-LAla) have been synthesized, and their antibacterial properties in vitro have been evaluated. The dipeptides 1, 3-6, and 8-17 and the tripeptide 20 are all broad-spectrum antibacterial agents with considerable potency against both Gram-positive and Gram-negative species, but none of these peptides improves dramatically on the antibiotic efficacy of the previously described beta-Cl-LAla-beta-Cl-LAla, 9 (Cheung, K. S.; Wasserman, S. A.; Dudek, E.; Lerner, S. A.; Johnston, M. J. Med. Chem. 1983, 26, 1733). Gram-negative microorganisms, such as Escherichia coli, Hemophilus influenzae, Shigella flexneri, and Enterobacter species are consistently resistant to any haloalanyl peptide containing an alanyl residue, such as the dipeptide LAla-beta-Cl-LAla (2) and the tripeptides LMet-LAla-beta-Cl-LAla (7), LAla-LAla-beta-Cl-LAla (18), and LVal-LAla-beta-Cl-LAla (19). Correspondingly, these same organisms are protected from the bactericidal effects of 9 by supplementation of the growth medium with LAla or LAla-LAla. Escherichia coli JSR-O exposed to 9, but protected from lysis by sucrose stabilization, has only about 10% the normal level of intracellular alanine racemase activity. But when these cells are cultured in the presence of 9 with LAla supplementation, or in the presence of 2 with no supplementation, the alanine racemase levels are only about 20-30% below control values. These findings suggest that the resistance of Gram-negative species to chloroalanyl peptides containing alanyl units arises from the ability of LAla to protect the targeted racemase from inactivation by beta-Cl-LAla in vivo, an event which otherwise leads to cell death and lysis. Inactivation of alanine racemase in Gram-positive organisms appears not to be the cellular event that confers sensitivity of these species to a haloalanyl peptide.
Asunto(s)
Alanina Racemasa/antagonistas & inhibidores , Alanina/análogos & derivados , Alanina/farmacología , Isomerasas de Aminoácido/antagonistas & inhibidores , Antibacterianos/farmacología , Dipéptidos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Oligopéptidos/farmacología , beta-Alanina/análogos & derivados , Antibacterianos/síntesis química , Bacterias Gramnegativas/enzimología , Oligopéptidos/síntesis química , Transaminasas/antagonistas & inhibidores , beta-Alanina/farmacologíaRESUMEN
The enzyme responsible for the transamination of L-asparagine in pea leaves has been partially purified. It appears to be the same protein as the serine-glyoxylate aminotransferase. It is able to use serine or asparagine as amino donors and pyruvate or glyoxylate as amino acceptors. The reaction is reversible but the equilibrium is toward glycine or alanine production. The favored substrates are serine and glyoxylate: serine shows competitive inhibition toward asparagine, as does pyruvate toward glyoxylate. Substrate interaction and product inhibition patterns are consistent with a ping-pong mechanism. The enzyme has a pH optimum at 8.1. Gel filtration indicates a Mr of 105,000. Inhibition was caused by aminoxyacetate and hydroxylamine, but the enzyme was unaffected by isonicotinic acid hydrazide. The apoenzyme was resolved and was inactive: addition of pyridoxal 5'-phosphate restored 85% of the original activity.
Asunto(s)
Fabaceae/enzimología , Plantas Medicinales , Transaminasas/aislamiento & purificación , Asparagina , Glioxilatos/aislamiento & purificación , Glioxilatos/metabolismo , Concentración de Iones de Hidrógeno , Fosfato de Piridoxal/metabolismo , Serina/aislamiento & purificación , Serina/metabolismo , Especificidad por Sustrato , Transaminasas/antagonistas & inhibidores , Transaminasas/metabolismoAsunto(s)
4-Aminobutirato Transaminasa/antagonistas & inhibidores , Aminocaproatos/administración & dosificación , Encéfalo/metabolismo , Transaminasas/antagonistas & inhibidores , Ácido gamma-Aminobutírico/biosíntesis , Animales , Cuerpo Estriado/metabolismo , Lóbulo Frontal/metabolismo , Glutamato Descarboxilasa/metabolismo , Cinética , Masculino , Métodos , Terminaciones Nerviosas/fisiología , Ratas , Ratas Endogámicas , Sustancia Negra/metabolismo , Colículos Superiores/metabolismo , VigabatrinRESUMEN
Cefazolin given sc to male rats in daily doses of 0.5-2 g per kilogram of body weight significantly decreased alanine aminotranferase activity in serum, liver, kidney, heart, and brain 2-4 wk from the beginning of the treatment. Serum aspartate aminotransferase was also reduced, but serum alkaline phosphatase and tissue pyruvate decarboxylase activities remained unaltered. In female rats, daily sc administration of cefazolin at 0.1-1 g/kg also brought about a dose-related reduction of alanine and aspartate aminotransferase activities, which reached statistical significance at high dose levels. The effect of cefazolin at low concentrations was partly reversed by administration of pyridoxal in vivo. Paradoxically, at higher dose levels pyridoxal potentiated the action of cefazolin on serum aminotranferases. The low enzyme activities were elevated by subsequent addition of pyridoxal 5'-phosphate in vitro. Similar results were obtained when rats were treated with isoniazid at daily oral doses of 200 mg/kg; administration of pyridoxal completely restored alanine aminotransferase activity to the normal level within 2 wk. Cefazolin was metabolized in vivo, resulting in some metabolites that probably possessed a hydrazine group, since positive reactions were obtained with p-dimethylaminobenzaldehyde and Fast Blue B salt. The potentiation of decreased aminotransferase activity by pyridoxal indicated, however, some dissimilarity in the effect between isoniazid and cefazolin.
Asunto(s)
Cefazolina/efectos adversos , Transaminasas/antagonistas & inhibidores , Alanina Transaminasa/antagonistas & inhibidores , Animales , Cefazolina/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Isoniazida/efectos adversos , Masculino , Piridoxal/farmacología , Piridoxina/análisis , RatasRESUMEN
A decrease in brain GABA concentration has been implied as the cause of convulsions induced by hyperbaric oxygen (HOP). We therefore examined the influence of sodium valproate, an anticonvulsant and GABA transaminase inhibitor on HOP-induced convulsions in rats. The mean latency of occurrence of the first electrical discharge in the ECoG and the appearance of the first clinical seizure in awake chronically implanted rats was unchanged by administration of sodium valproate prior to HOP exposure. We conclude that either the sodium valproate inhibition of GABA removal is insufficient to compensate for HOP inhibition of its production, or else that GABA concentration changes are not causally related to HOP-induced seizures.
Asunto(s)
4-Aminobutirato Transaminasa/antagonistas & inhibidores , Oxigenoterapia Hiperbárica/efectos adversos , Convulsiones/tratamiento farmacológico , Transaminasas/antagonistas & inhibidores , Valeratos/uso terapéutico , Ácido Valproico/uso terapéutico , Animales , Electroencefalografía , Masculino , Ratas , Convulsiones/etiología , Convulsiones/fisiopatología , Ácido Valproico/farmacologíaRESUMEN
Several aryl and heteroaryl hydrazides were synthesized and evaluated for their inhibitory effects on glutamic acid decarboxylase (GAD), GABA-alpha-oxoglutarate aminotransferase (GABA-T), and monoamine oxidase (MAO) enzyme systems in chick brain 24 h after their intramuscular administration (0.75 mmol/kg). All compounds produced a reduction in GAD, GABA-T, and MAO activity. Structure-activity relationships indicated that the ring structure had a greater influence on the degree of GAD and GABA-T inhibition than did the N'-terminal group. In contrast, structural requirements for MAO inhibition were much more restrictive. The intramuscular administration of benzoic acid hydrazide to chicks 24 h prior to their being exposed to oxygen at high pressure provided significant protection against the onset of the hyperbaric oxygen-induced seizures.