RESUMO
Previous studies evidenced that garlic extracts and/or garlic components were able to prevent against chemically induced tumors or acute toxic effects of chemicals (e.g. CCl4 induced liver injury). The chemopreventive potential of garlic has been attributed to the presence in it of several bioactive organosulfur compounds. Those components might act as antioxidants able to scavenge free radicals. In the present work we describe initial studies on the antioxidative-stress properties of some garlic components such as: diallyl disulfide (DDS), diallyl sulfide (DAS), allyl mercaptan (AMT) and allyl methyl sulfide (AMS). We found that DAS, DDS and AMT but not AMS were able to trap trichloromethyl and trichloromethylperoxyl free radicals. Further, DDS but not DAS or AMT also inhibited CCl4 promoted liver microsomal lipid peroxidation. DAS, but not DDS, AMT or AMS was able to react with free radicals arised during UVC activation of hydrogen peroxide or terbutyl hydroperoxide but not with those produced during UVC activation of terbutyl peroxide. However, all garlic components tested absorbed energy from UVC and became partially destroyed in the process. AMT, but not DDS, AMS or DAS was able to destroy 4-hydroxynonenal, a key reactive aldehyde produced during lipid peroxidation. AMT and DDS were also able to prevent UVC plus CCl4 promoted oxidation of albumin in vitro, but DAS and AMS failed to do so. Results suggest that the antioxidative stress properties of garlic might result from the contributions of its sulfur component in different steps and not necessarily from the contribution of only one of them.
Assuntos
Compostos Alílicos/farmacologia , Tetracloreto de Carbono/toxicidade , Alho/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Plantas Medicinais , Compostos Alílicos/antagonistas & inibidores , Animais , Radicais Livres , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Raios UltravioletaRESUMO
Nifurtimox (Nfx) 4-[(5-nitrofurfurylidine)amino-3-methylthiomorpholine-1-1-di oxide] is a drug that is being used to treat American Trypanosomiasis (Chagas' disease). Nfx has serious toxic effects including mutagenic, reproductive and carcinogenic actions. Its toxicity has been linked to NADPH dependent nitroreductive metabolic biotransformation with production of oxygen reactive species. In this study is reported that rat liver nuclei exhibit Nfx-nitroreductase activity (Nfx-ase). This activity is null under oxygen and partially inhibited under CO. Nfx does not promote a lipid peroxidation process. Results suggest that Nfx is biotransformed partially at a cytochrome P450 level but mostly by NADPH P450 reductase. Formation of reactive metabolites nearby DNA and nuclear proteins might be related to long term deleterious effects of this drug.
Assuntos
Fígado/enzimologia , Nifurtimox/farmacologia , Nitrorredutases/metabolismo , Animais , Biotransformação , Monóxido de Carbono , Núcleo Celular/enzimologia , Sistema Enzimático do Citocromo P-450/metabolismo , Ativação Enzimática/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , NADP/farmacologia , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Nifurtimox/farmacocinética , Oxigênio , Ratos , Ratos Sprague-Dawley , Espécies Reativas de OxigênioRESUMO
Depression of liver microsomal glucose-6-phosphatase (G6Pase) activity is a relevant feature of CCl4 poisoning. In vitro studies from several laboratories led to the hypothesis that a CCl4 promoted lipid peroxidation (LP) process is responsible for that effect. In vivo studies from our laboratory with potent antioxidants in dosage regimes inhibiting LP, however, were in contrast with that hypothesis. In this work we studied the potential preventive effects of Pyrazole (Pyr), alpha-tocopherol (alpha T), and 3-amino-1,2,4-triazole (AT) against CCl4-induced depression of G6Pase activity. Pyr decreases the intensity of the covalent binding (CB) of CCl4 reactive metabolites to cellular components but does not inhibit LP in vitro or in vivo. alpha T inhibits LP in vitro and in vivo and AT inhibits both CB and LP. Our present studies give evidence that AT but neither Pyr nor alpha T are able to prevent the CCl4-induced depression of G6Pase activity. Results are compatible with the hypothesis that the cooperation of both factors is critical to explain the observed effects, and suggest that under in vitro experimental conditions used by others the relevance of LP might be artifactually promoted.
Assuntos
Intoxicação por Tetracloreto de Carbono/metabolismo , Glucose-6-Fosfatase/metabolismo , Peroxidação de Lipídeos , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Pirazóis/farmacologia , Vitamina E/metabolismo , Amitrol (Herbicida)/farmacologia , Animais , Tetracloreto de Carbono/toxicidade , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Vitamina E/farmacologiaRESUMO
The rate of reaction of several radioprotective agents or their active metabolites with 4-hydroxynonenal (4HNE) was studied and compared to the rate of reaction with cysteine (Cys) and glutathione (GSH). The agents studied were: mercapto ethylamine (MEA); 2(3-aminopropyl) aminoethanethiol (WR1065); S-2-aminoethylisothiouronium bromide-hydrobromide (AET); 1,4-dithiothreitol (DTT); 1,4-dithioerythritol (DTE); N-2(2-mercaptopropionyl)-glycine (MPG); penicillamine hydrochloride (PA); N-acetylcysteine (NAC); 2-3 dimercapto-1 propane sulfonic acid (DMPS); 2,3-dimercaptopropanol (BAL), and meso 2,3 dimercapto succinic acid (DMS). All of them reacted with 4HNE. MEA and WR1065 were the most reactive thiols, and PA and DMS were the least reactive thiols. All the others reacted at rates comparable to or higher than that of cysteine or GSH. The potential role of this type of interactions in the protective action of these drugs against deleterious effects of radiation or carbon tetrachloride is analyzed.
Assuntos
Aldeídos/química , Protetores contra Radiação/química , Cisteína/química , Glutationa/química , Cinética , Compostos de Sulfidrila/químicaRESUMO
We have previously reported that treatments stimulating phospholipid (PL) synthesis or preventing PL degradation were late preventive agents against CCl4-induced liver necrosis. Later studies by others postulated that stimulation of phospholipase A2 (PLA2) plays a role in PL degradative processes responsible for CCl4 damage. Quinacrine (QUIN) is a well known inhibitor of PLA2. In this work we report that QUIN (150 mg/kg i.p.) partially prevents CCl4-induced liver necrosis at 24 h when given 30 min before or 6 or 10 h after CCl4 (2.5 ml/kg p.o.) QUIN administration does not modify at 1 or 3 h after poisoning CCl4 levels reaching the liver, covalent binding of CCl4 reactive metabolites to proteins or lipids, CCl4-induced lipid peroxidation process, CCl4-induced decreases in body temperature, or glutathione levels in liver. QUIN concentrations in liver at times from 1 to 24 h are well over those required to inhibit PLA2 activity. Results are compatible with the hypothesis that CCl4 activation of PLA2 at late stages of poisoning plays a role in CCl4-induced liver necrosis.
Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Hepatopatias/prevenção & controle , Fígado/patologia , Quinacrina/uso terapêutico , Animais , Temperatura Corporal/efeitos dos fármacos , Cálcio/metabolismo , Radioisótopos de Carbono , Tetracloreto de Carbono/metabolismo , Glutationa/metabolismo , Metabolismo dos Lipídeos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Necrose/induzido quimicamente , Fosfolipases A/metabolismo , Fosfolipases A2 , Fosfolipídeos/metabolismo , Ligação Proteica , Proteínas/metabolismo , Quinacrina/metabolismo , Quinacrina/farmacocinética , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole acetamide) is a drug used against Chagas' disease, a parasitic disease afflicting several millions of Latin Americans. Bz administration to Sprague-Dawley male rats at 100 mg/kg p.o. caused subcellular alterations in the adrenal cortex involving fasciculata and reticularis zones but not in the glomerulosa. There is Bz nitroreductase activity in the adrenal microsomal and mitochondrial fractions but most of it is localized in mitochondria. Activity in the two fractions requires NADPH under anaerobic conditions. Mitochondrial Bz nitroreductase activity was inhibited by oxygen. A minor but statistically significant inhibition was observed in mixtures incubated under carbon monoxide. Microsomal Bz nitroreductase activity was not detected under oxygen atmosphere and was not inhibited under carbon monoxide. No Bz nitroreductase activity mediated by xanthine oxidase or aldehyde oxidase was detected in the cytosolic fraction from rat adrenals. Electron microscopic examination of the adrenal cortex from Bz-treated animals revealed cells with marked lipid accumulation and alterations in nuclei, endoplasmic reticulum and mitochondria in the reticularis and fasciculata zones. In vitro results suggest a Bz nitroreductive activation, with minor or null P-450 participation, leading to reactive metabolites able to cause damage in various organelles.
Assuntos
Córtex Suprarrenal/efeitos dos fármacos , Nitroimidazóis/toxicidade , Nitrorredutases/análise , Administração Oral , Córtex Suprarrenal/ultraestrutura , Animais , Masculino , Microscopia Eletrônica , Microssomos/enzimologia , Mitocôndrias/enzimologia , Mutagênicos/toxicidade , Nitroimidazóis/administração & dosagem , Ratos , Ratos Endogâmicos , Frações Subcelulares/enzimologiaRESUMO
El antichagásico Benznidazol presenta efectos tóxicos indeseables en su empleo clínico. Esta droga es capaz de pasar al lactante vía leche materna modificando su capacidad metabolizante de xenobióticos. En ratas lactantes cuyas madres fueron tratadas previamente con la droga el tiempo de sueño producido por pentobarbital fue modificado, así como también la actividad de la aminopirina demetilasa, que fue significativamente menor que en ratas lactantes control.
Assuntos
Humanos , Gravidez , Ratos , Animais , Masculino , Feminino , Animais Lactentes/metabolismo , Leite Humano/efeitos dos fármacos , Nitroimidazóis/efeitos adversos , Aminopirina N-Desmetilase , Biotransformação , Citocromos , Microssomos Hepáticos , Nitroimidazóis/metabolismo , Pentobarbital , Ratos Endogâmicos/metabolismo , Sono , Tripanossomicidas/efeitos adversosRESUMO
El antichagásico Benznidazol presenta efectos tóxicos indeseables en su empleo clínico. Esta droga es capaz de pasar al lactante vía leche materna modificando su capacidad metabolizante de xenobióticos. En ratas lactantes cuyas madres fueron tratadas previamente con la droga el tiempo de sueño producido por pentobarbital fue modificado, así como también la actividad de la aminopirina demetilasa, que fue significativamente menor que en ratas lactantes control. (AU)
Assuntos
Humanos , Gravidez , Ratos , Animais , Masculino , Feminino , Nitroimidazóis/efeitos adversos , Animais Lactentes/metabolismo , Leite Humano/efeitos dos fármacos , Nitroimidazóis/metabolismo , Pentobarbital , Ratos Endogâmicos/metabolismo , Aminopirina N-Desmetilase , Citocromos , Tripanossomicidas/efeitos adversos , Sono/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Biotransformação/efeitos dos fármacosRESUMO
Nifurtimox (Nfx) (4(5-nitrofurfurylidene)amino)-3-methylthiomorpholine-1, 1-dioxide) is a drug used against Chagas' disease, a parasitic sickness afflicting several million Latin Americans. Nfx administration to Sprague-Dawley male rats (220-250 g) at a dose of 100 mg/kg caused pronounced alterations in the adrenal cortex involving the fasciculata and reticularis zones but which were not evident in the glomerulosa. Alterations observed involved mitochondria, nuclei, Golgi apparatus, and the endoplasmic reticulum but were more intense in the mitochondria. There is Nfx nitroreductase activity in the adrenal microsomal, mitochondrial, and cytosolic-rich fractions but most of it is in the mitochondrial-rich fraction. Activity in the first two fractions requires NADPH and that in the cytosol is only observed in the presence of hypoxanthine as substrate. Enzymatic activity in all fractions is inhibited by oxygen. CO does not inhibit mitochondrial Nfx nitroreductase and inhibits only 10% of the microsomal enzyme activity. Hypoxanthine-dependent cytosolic activity is inhibited by allopurinol. Present results suggest that Nfx is activated to damage-producing reactive metabolites by nitroreductive biotransformation in rat adrenal organelles. Mitochondrial and microsomal bioactivation would occur at the level of the flavoenzyme P-450 reductase rather than at P-450 itself, and cytosolic bioactivation would be mediated by xanthine oxidase. Epidemiological studies on adrenal function in patients undergoing Nfx treatment would be necessary to establish the potential toxicological relevance of these findings.
Assuntos
Córtex Suprarrenal/ultraestrutura , Nifurtimox/farmacologia , Nitrofuranos/farmacologia , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Animais , Biotransformação/efeitos dos fármacos , Biotransformação/fisiologia , Dióxido de Carbono/metabolismo , Citosol/enzimologia , Masculino , Microscopia Eletrônica , Microssomos/enzimologia , Mitocôndrias/enzimologia , Nifurtimox/metabolismo , Nifurtimox/farmacocinética , Nitrogênio/metabolismo , Nitrorredutases/metabolismo , Oxirredução/efeitos dos fármacos , Oxigênio/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Chagas' disease is a parasitic chronic condition affecting several million people in Latin America. Two drugs are used in the chemotherapy of Chagas' disease: nifurtimox (Nfx) and benznidazole (Bz). Both are nitroderivatives whose deleterious effects are related to their reductive biotransformation. In this work we report that rat ovaries exhibited Bz and Nfx nitroreductase activity. The Bz nitroreductase was only found in the mitochondrial fraction and was partially inhibited by CO. The Nfx nitroreductase activity was maximal in ovarian mitochondria but was also present in microsomes and in the cytosol. The microsomal enzyme was completely inhibited by CO while that in mitochondria was only partially inhibited by CO. The cytosolic activity only proceeded using hypoxanthine as substrate and was inhibited by allopurinol. The cytosolic activity was able to proceed in part under oxygen. All the other Bz or Nfx nitroreductases were completely inhibited by atmospheric oxygen. The potential participation of cytochrome P450, flavoenzymes, iron-sulfur-protein, and xanthinooxidase in both nitroreductive processes is discussed. The administration of either Nfx or Bz to female rats produced ultrastructural degenerative effects in the different cell types of ovaries. Specific alterations such as swelling, disruption, disorganization, and loss of matrix components were observed in ovarian mitochondria. These alterations occurred irrespectively of the ovarian cycle stage. The potential reproductive toxicological consequences of Bz or Nfx administration are analyzed.
Assuntos
Nifurtimox/toxicidade , Nitrofuranos/toxicidade , Nitroimidazóis/toxicidade , Nitrorredutases/metabolismo , Ovário/efeitos dos fármacos , Oxirredutases/metabolismo , Tripanossomicidas/toxicidade , Animais , Biotransformação , Citosol/enzimologia , Feminino , Microscopia Eletrônica , Microssomos/enzimologia , Mitocôndrias/enzimologia , Nifurtimox/farmacocinética , Nitroimidazóis/farmacocinética , Ovário/enzimologia , Ovário/metabolismo , Ovário/ultraestrutura , Ratos , Ratos Endogâmicos , Tripanossomicidas/farmacocinéticaRESUMO
Epimastigotes of Trypanosoma cruzi (Tulahuen strain Tul 0 stock) biotransform benznidazole (N-benzyl-2-nitro-1-imidazole acetamide) to reactive metabolites that bind covalently to DNA, proteins and lipids of the parasite. These effects might be related to the trypanocidal action of benznidazole, a chemotherapeutic agent against Chagas' disease.
Assuntos
DNA/metabolismo , Metabolismo dos Lipídeos , Nitroimidazóis/metabolismo , Proteínas/metabolismo , Trypanosoma cruzi/análise , Animais , Núcleo Celular/análiseRESUMO
American trypanosomiasis (Chagas' disease) is an endemic parasitic disease afflicting more than 20 million persons in Latin America. Two drugs are currently being used for treatment of the acute phase of Chagas' disease: 4-[(5-nitrofurfurylidene)amino-3-methylthiomorpholine-1,1-di oxide] (Nifurtimox; Nfx) and (N-benzl-2-nitro-1-imidazole acetamide) (Benznidazole; Bz). Nfx and Bz have serious undesirable effects, which have been reported during their clinical use, including anorexia and weight loss, nausea and vomiting, nervous excitation, insomnia, psyche depressions, convulsions, vertigo, headache, sleepiness, myalgias, arthralgias, loss of balance, disorientation, forgetfulness, paresthesias, adynamia, acoustic phenomena, peripheral neuropathies, gastralgia, mucosal edema, hepatic intolerance, skin manifestations, and intolerance to drinking alcohol. Effects in the central and peripheral nervous system of Nfx were also reproduced in animals. Signs of testicular and ovarian injury were reported for both Nfx and Bz, the effects of Bz being in general less intense than those of Nfx. Both drugs evidenced mutagenicity. In light of the present knowledge about the toxicity of Nfx and Bz, further studies on the mutagenic, teratogenic, carcinogenic, and reproductive effects of both drugs are recommended. Lack of information is particularly serious for Bz. Studies on Nfx and Bz biotransformation, activation to reactive metabolites, and potential mechanisms for their toxic effects were analyzed. Risk-benefit considerations of the use of Nfx and Bz were made and an analysis of the need for research on Chagas' disease chemotherapy was also performed.
Assuntos
Doença de Chagas/tratamento farmacológico , Nifurtimox/efeitos adversos , Nitrofuranos/efeitos adversos , Nitroimidazóis/efeitos adversos , Humanos , América Latina , Nifurtimox/uso terapêutico , Nitroimidazóis/uso terapêuticoRESUMO
Nifurtimox (Nfx) and Benznidazole (Bz) are 2 drugs used in the chemotherapy of Chagas' disease, a sickness afflicting millions of Latin Americans. Their toxicity is related to nitroreductive activation. Nfx and Bz nitroreductase activity in liver microsomes from male rats is already present at low levels in the newborn and reaches full adult activity in 28 days. This suggests a better therapeutic approach by starting the treatment of transplacentally acquired Chagas' disease immediately after birth.