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Biomedical subjects

E G de Toranzo

Publications and source records attributed to E G de Toranzo.

At least 19 recordsLinked to original sources
PubMed1998

Mechanisms of the preventive properties of some garlic components in the carbon tetrachloride-promoted oxidative stress. Diallyl sulfide; diallyl disulfide; allyl mercaptan and allyl methyl sulfide.

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.

Allyl Compounds↗
PubMed1997

Rat liver nuclear nifurtimox nitroreductase activity.

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.

Animals↗
PubMed1996

Depression of liver microsomal glucose 6-phosphatase activity in carbon tetrachloride-poisoned rats. Potential synergistic effects of lipid peroxidation and of covalent binding of haloalkane-derived free radicals to cellular components in the process.

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.

Amitrole↗
PubMed1994

Reaction of 4-hydroxynonenal with some thiol-containing radioprotective agents or their active metabolites.

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.

Aldehydes↗
PubMed1993

Late preventive effects of quinacrine on carbon tetrachloride induced liver necrosis.

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.

Animals↗
PubMed1989

Ultrastructural alterations in ovaries from nifurtimox or benznidazole-treated rats: their relation to ovarian nitroreductive biotransformation of both drugs.

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.

Animals↗
PubMed1987

Effects of carbon tetrachloride on the liver of chickens. Early biochemical and ultrastructural alterations in the absence of detectable lipid peroxidation.

Administration of CCl4 i.p. to Leghorn chickens did not promote lipid peroxidation of liver microsomal lipids, as evidenced by either increased diene conjugation or by decreased arachidonic acid content. The hepatotoxin did not produce liver necrosis 24 h after dosing, but decreased the cytochrome P-450 content, and aminopyrine N-demethylase and glucose 6 phosphatase activities at 1, 3, 6 and 24 h. CCl4 administration produced dilation of the rough endoplasmic reticulum and detachment of ribosomes from their membranes. These observations suggest that lipid peroxidation is not the key event in the production of these biochemical and ultrastructural alterations, elicited by CCl4.

Aminopyrine N-Demethylase↗
PubMed1987

Liver microsomal benznidazole and nifurtimox nitroreductase activity in male rats of different age.

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.

Aging↗
PubMed1987

Species and sex differences in the liver microsomal nitroreductive biotransformation of nifurtimox and benznidazole.

Nifurtimox (NFX) and Benznidazole (Bz) are two drugs effective against acute Chagas' disease. Both have considerable toxic side effects related to nitroreductive biotransformation. In this work, we studied the species and sex differences in liver microsomal NFX (NFX-ase) and Bz nitroreductase activity (Bz-ase). Animal species tested were rats, mice, hamsters and guinea-pigs. Bz-ase is significantly higher in male rats and hamsters than in females. No significant sex difference was observed in mice or guinea-pigs. Bz-ase in the males is: hamsters greater than mice greater than guinea-pig approximately equal to rat and in females it is: mice approximately equal to guinea-pig approximately equal to hamster greater than rat. NFX-ase is higher in either male rats or female mice than in either female rats or male mice. No sex difference was observed in the other species. In males NFX-ase is: hamsters approximately equal to mice greater than rat approximately equal to guinea-pig, while in females it is mice approximately equal to hamsters greater than guinea-pig approximately equal to rat. Results suggest that hamsters and mice might be the most suitable species to study toxic effects related to their liver microsomal nitroreductive biotransformation. This might be of particular relevance for carcinogenicity studies.

Animals↗
PubMed1986

Effects of nifurtimox or benznidazole administration on rat testes: ultrastructural observations and biochemical studies.

Ultrastructural and biochemical alterations in testes of Sprague-Dawley rats receiving either nifurtimox (Nfx) or benznidazole (Bz) (both 100 mg/kg po) were studied. Nfx produced intense deleterious effects on Steroli cells consisting of dilatation of endoplasmic reticulum and perinuclear membrane, alterations in shape and size of mitochondria, increased lysosomal activity, detachment of ribosomes, and alterations in shape and configuration of spermatids and mature spermatozoa. Bz induced alterations were similar in nature but far less intense and observable only in some cells or preparations or animals but not in others. Testicular Nfx but not Bz nitroreductase activity was detected in microsomal and cytosolic fractions. Microsomal Nfx nitroreductase activity was not inhibited by CO. The cytosolic activity in the presence of hypoxanthine was inhibited by allopurinol and that in the presence of N-methylnicotinamide was inhibited by menadione. All these enzymatic activities were inhibitable by oxygen except the cytosolic one in the presence of N-methylnicotinamide. No evidence for lipid peroxidation was found in testes from Nfx treated animals. Covalent binding of Bz reductive metabolites to testicular proteins and phospholipids was found. Toxicological and pharmacological implications for patients suffering Chagas' disease and receiving these drugs were analyzed.

Animals↗
PubMed1985

Benznidazole and nifurtimox nitroreductase activity in liver microsomes from male rats preinduced with phenobarbital or 3-methylcholanthrene.

Liver microsomes from Sprague-Dawley male rats are able to biotransform Benznidazole (Bz) or Nifurtimox (NFX) by nitroreduction. Pretreatment of the rats during three days with phenobarbital (80 mg/kg/day, ip) but not with 3-methylcholanthrene (35 mg/kg/day ip) increased both Bz and NFX nitroreductase activity. Results suggest that cytochrome P-450 but not cytochrome P-448 is involved in the nitroreduction of these two chemotherapeutic agents against Chagas' disease. Possible pharmacological and toxicological implications of these observations are discussed.

Animals↗
PubMed1985

Effect of benznidazole on the mixed function oxygenase system from rat liver microsomes.

Previous Benznidazole (Bz) administration to rats (30 mg/kg, i.p.) significantly prolongs their pentobarbital sleeping time. This prolonging effect of Bz administration correlates with the inhibitory action of Bz on the liver aminopyrine or ethylmorphine N-demethylase activities. Inhibition of these enzyme systems by Bz is non-competitive and would not be related to changes in liver microsomal cytochrome P-450 (P-450) content or in cytochrome c-reductase activity or to interactions of Bz with P-450 leading to spectral changes. Covalent interactions of Bz reactive metabolites with microsomal proteins or phospholipids might be involved instead.

Aminopyrine N-Demethylase↗
PubMed1984

Reductive metabolism and activation of benznidazole.

Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole-acetamide) is a drug used against Chagas' disease. Rat liver microsomal and cytosolic fractions, but not mitochondria, exhibited Bz nitroreductase activity under anaerobic conditions in the presence of NADPH. Microsomal nitroreductase activity was enhanced by FAD and was inhibited totally by oxygen and partially by carbon monoxide. Liver cystosol fraction was able to reduce Bz nitrogroups in the presence of either N-methylnicotinamide or hypoxanthine as substrates. These enzyme activities were inhibited by menadione or allopurinol respectively. Under every experimental condition leading to enzymatic reduction of Bz nitrogroups and its inhibition or enhancement, reactive metabolites that bind covalently to proteins were also produced. This covalent binding was effectively prevented by reduced glutathione. Results suggest the participation of cytochrome P-450 and cytochrome c reductase in liver microsomal processes and of xanthine oxidase and aldehyde oxidase in liver cytosolic processes of Bz nitroreduction and activation to reactive metabolites that bind covalently to proteins. Possible pharmacological and toxicological implications of the described observations were discussed.

Animals↗
PubMed1984

Administration of benznidazole, a chemotherapeutic agent against Chagas disease, to pregnant rats. Covalent binding of reactive metabolites to fetal and maternal proteins.

Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole acetamide) is one of the drugs used in the chemotherapy of Chagas' disease though there is scarce data at present about its toxicological properties. The aim of this study was to obtain some very preliminary information about the potential risks for the fetuses when Bz is administered to pregnant women. With that purpose, 14C-Bz was orally administered to rats at twenty days of pregnancy. The animals were sacrificed 1, 3 or 6 hr after administration and the different tissues and fetuses analyzed for 14C from 14C-Bz bound covalently to proteins. It was observed that the drug is readily absorbed, crosses the placental barrier and reaches the fetuses. It is also activated in vivo to reactive metabolites that bind covalently to maternal and fetal proteins. In the light of the present results it would be wise to carefully consider the need and unknown risk of Bz therapy in pregnant women, until further appropriate studies on the developmental toxicology of Bz become available.

Animals↗
PubMed1984

Studies on nifurtimox nitroreductase activity in liver and other rat tissues.

Rat liver microsomes exhibit nifurtimox (NFX) nitroreductase activity, which is mostly NADPH-dependent and is completely abolished by heating and under an atmosphere of air. Pure carbon monoxide inhibits for 28% microsomal NFX nitroreductase activity while FAD 1 mM significantly enhances it. Smaller activities than in liver were found in brain, small intestine, testes, lung and heart. Rat liver cytosol also showed NFX nitroreductase activity using either hypoxanthine or N-methylnicotinamide as substrates. These activities were inhibited by allopurinol or menadione respectively. Results suggest that cytochrome P-450, NADPH cytochrome c reductase, xanthinoxidase and aldehyde oxidase are able to reduce NFX nitrogroups in rat liver and other tissues.

Animals↗
PubMed1983

Nitroreduction of benznidazole and nifurtimox by rat and human feces.

Rat and human feces are able to reduce nitro group from Benznidazole (N-benzyl-2-nitro-1-imidazole acetamide) and Nifurtimox (4[5-nitrofurfurylidene)-amino)-3-methylthiomorpholine-1,1-dioxide), two chemotherapeutic agents against Chagas' disease. Feces from rats treated with neomycin sulfate lack nitroreductase activity evidencing the bacterial origin of the enzyme.

Animals↗
PubMed1982

Covalent binding of carbon tetrachloride metabolites to the heme moiety of cytochrome P-450 and its degradation products.

Trichloromethyl free radicals (. CCI) produced during a benzoyl peroxide decomposition of CCl4 covalently bind to hemin. Enzymatically produced . CCl3 by an NADPH anaerobic liver microsomal activation of CCl4, covalently binds to heme and heme degradation products from CO-binding particles. 14C from CCl4 covalently binds to heme and heme degradation products from liver CL-binding particles from rats treated with 14CCl4. In vivo covalent binding of 14CCl4 reactive metabolites to proteins from CO-binding particles is higher than that to the whole microsomal proteins. The possible correlation between binding of . CCl3 to heme and protein moieties of P-450 and CCl4 induced P-450 destruction is discussed.

Animals↗