Biomedical subjects

J A Castro

Publications and source records attributed to J A Castro.

At least 145 records · Page 8Linked to original sources

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 the administration of 5,6-dihydroxytryptamine to the amygdala and dorsal raphe nucleus on plasma renin activity].

The effect of injections of 5,6-dihydroxytryptamine, a potent and selective neurotoxic of serotonin neurons, into amygdala and dorsal raphe mesencephalic nucleus on the plasma renin activity has been studied in male Wistar rats. Plasma renin activity was estimated on 2nd, 4th, Tth and 14th day after injections in both areas. The administration of 5,6-dihydroxytryptamine in amigdala produced a significant decrease in plasmatic renin activity between 2nd and 4th day, but the inverse effect between 7th and 14th day. Similar effects were found after injections in dorsal raphe nucleus. The contents of cerebral 5-HT were simultaneously evaluated in the entire brain when the drug was implanted in dorsal raphe, and only in amygdaloid tissue when the injection was restricted to this area. A significant decrease in serotonin content was produced 7th day in both places, while partial recuperation was found toward 14th day. The results, especially the ones related to the chemical lesion of dorsal raphe nucleus, suggest that serotoninergic brain systems are involved, as stimulators, in the control of the dynamics of renin-angiotensin system.

5,6-Dihydroxytryptamine↗

PubMed1985

Late preventive effects of several anticalmodulin drugs on galactosamine-induced liver necrosis.

Four anticalmodulin drugs: trifluoperazine (TFP), pimozide (PMZ), thioridazine (TDZ) and imipramine (IMP) (50 mg/kg, ip) were able to partially prevent Galactosamine (GAL) (600 mg/kg, ip) induced liver necrosis when given 6 h after the hepatotoxin. IMP was also effective 10 h after GAL. The possibility of calmodulin participation in late stages of GAL-induced liver injury is analyzed.

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

Carbon tetrachloride activation by highly purified liver mitochondrial preparations.

Highly purified rat liver mitochondrial preparations were found to be able to activate CCl4 to reactive metabolites that bind covalently to lipids. Part of the process is of an enzymatic nature, but most of it is non-enzymatic. The enzymatic mitochondrial CCl4 activation operates more efficiently under anaerobic conditions; it requires NADPH, is CO sensitive, is inducible by phenobarbital pretreatment and is only weakly inhibited by high concentrations of cyanide or azide. The non-enzymatic mitochondrial CCl4 activation is not inhibited by CO and proceeds equally well under air or nitrogen.

Animals↗

PubMed1984

Carbon tetrachloride-induced early biochemical alterations but not necrosis in pigeon's liver.

In contrast to what is well known to occur in rats, pigeons receiving CCl4 (1 ml/kg i.p.) were not susceptible to necrogenic effects of the hepatotoxin at 24 h. There were, however, other early biochemical alterations observable, such as depression of glucose 6 phosphatase activity, decrease in the cytochrome P-450 content and in aminopyrine-N-demethylase activity in pigeon liver microsomes at 3 and 6 h after CCl4 administration. Pigeon liver was able to activate CCl4 to reactive metabolites that bind covalently to lipids, but no CCl4-induced lipid peroxidation was proved by the diene hyperconjugation technique in pigeon liver microsomes at 1, 3 or 6 h after administration. Results suggest that covalent binding of CCl4-reactive metabolites are more relevant to early biochemical alterations induced by CCl4 than is lipid peroxidation. Absence of CCl4-induced necrosis in pigeon liver could be attributable to a smaller intensity of covalent binding interactions observed, when compared to susceptible species, and to absence of lipid peroxidation.

Aminopyrine N-Demethylase↗

PubMed1984

Late preventive effects of phenylmethylsulfonyl-fluoride on carbon tetrachloride-induced liver necrosis.

The administration to rats of phenylmethylsulfonylfluoride (PMSF) 6 or 10 h after tetrachloride (CCl4) significantly prevented liver necrosis induced by this hepatotoxin at 24 h but not at 72 h. Preventive effects of PMSF were not due to interference with CCl4 absorption from the peritoneum since CCl4 levels in livers of treated and untreated animals were not significantly different. The present and previous results from our laboratory suggest that degradative processes mediated by proteases and esterases might play a role in late reversible stages of CCl4-induced liver cell injury.

Animals↗

PubMed1984

Effect of cystamine on protein, phospholipid and RNA synthesis or degradation.

Cystamine administration to rats partially inhibited (14C)-leucine incorporation to microsomal proteins, and (14C) orotic acid incorporation to RNA but markedly stimulated (32P) incorporation to liver microsomal phospholipids. Cystamine administration did not modify the decay of radioactivity of liver microsomal lipids prelabeled with (32P) or of microsomal protein prelabeled with [(14C)-guanidino]arginine. Notwithstanding cystamine increased the RNA content in total liver. Results suggest that cystamine inhibits protein synthesis, stimulates phospholipid synthesis and inhibits RNA synthesis and degradation.

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

Metabolism and activation of 1,1-dimethylhydrazine and methylhydrazine, two products of N-nitrosodimethylamine reductive biotransformation.

N-Nitrosodimethylamine (NDMA) and two of its metabolites, monomethylhydrazine (MMH) and 1,1-dimethylhydrazine (UDMH) were metabolized to carbon dioxide by rat liver slices. Under these conditions, NDMA and MMH, but not UDMH, produced reactive metabolites that bound covalently to nucleic acids. Rat liver microsomes or 9000 X g supernatants were able to transform NDMA, MMH and UDMH to formaldehyde. In the case of MMH and UDMH, enzymatic and non-enzymatic pathways of formaldehyde formation were present in both liver microsomes and 9000 X g supernatants. NDMA, MMH and UDMH led to covalent binding in incubation mixtures containing either microsomes or 9000 X g supernatants. In the case of NDMA, the process was enzymatic and required NADPH in both cellular fractions. In the case of MMH, the process was enzymatic in microsomes, and required NADPH and oxygen when using UDMH or MMH and 9000 X g supernatants; interactions of a non-enzymatic nature leading to covalent binding to proteins were dominant. These results suggest that part of the carbon dioxide produced during NDMA metabolism might derive from UDMH and MMH. Similarly, a significant part of the covalent binding of NDMA metabolites to proteins in incubation mixtures containing microsomes or 9000 X g supernatants might derive from enzymatic and non-enzymatic reactions of UDMH or MMH. Also, a minor part of the covalent binding of NDMA reactive metabolites to nucleic acids might be due to further biotransformation of MMH to reactive metabolites. It may be concluded from the present results that biotransformation of NDMA to UDMH and MMH might not be a detoxication process, as previously thought, but one related to some of the toxic effects of NDMA.

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↗

PubMed1984

Late preventive effects on carbon tetrachloride-induced necrosis of the inhibitor of proteases 1-1-chloro-3-tosyl amido-7-amino-2-heptanone (TLCK).

The administration to rats of the inhibitor of proteases 1-1-chloro-3-tosyl-amido-7-amino-2-heptanone (TLCK) 6 or 10 h after carbon tetrachloride (CCl4), significantly prevented liver necrosis induced by this hepatotoxin at 24 h. The present and previous results from our laboratory suggest that degradative processes mediated by proteases and esterases might play a role in late stages of CCl4-induced liver cell injury.

Amino Acid Chloromethyl Ketones↗

PubMed1983

No response of pigeon liver to dimethylnitrosamine acute effects.

No evidence for liver necrosis was observed at 24, 48 or 72 h after injection of dimethylnitrosamine (DMN) (70 mg/kg, i.p.) to pigeons. The assessment of possible liver necrosis was made by determination of isocitric dehydrogenase (ICD), glutamate oxalacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) in plasma. The ability of pigeon liver slices to metabolize CO2 or to give covalent binding of reactive metabolites to nucleic acids was 24 times smaller than that for rat. Similarly, the pigeon liver microsomes or 9000 X g supernatant have DMN-demethylase activity or ability to activate DMN to reactive metabolites that bind covalently to proteins very close to zero. Results suggest that resistance of pigeon liver to DMN acute effects is related to its lack of ability for DMN metabolic activation.

Alanine Transaminase↗

PubMed1983

Modulation of galactosamine-induced liver injury by some amino acids or Triton WR1339.

Galactosamine administration to rats (600 mg/kg, i.p.) produces a severe liver necrosis at 24 h. Pretreatment with cystine, tryptophan or methionine (600 mg/kg, p.o., 30 min before the hepatotoxin) significantly prevents galactosamine-induced liver necrosis. Glutamic or aspartic acids, however, were not protective under a similar dosage regimen. The prior administration of Triton WR1339 (1 g/kg, i.v., 30 min before galactosamine) significantly enhanced the liver response to galactosamine-induced liver injury, whereas the administration of tyrosine resulted in death of the animals.

Amino Acids↗

PubMed1983

Prevention of thioacetamide-induced liver necrosis by prior administration of substrates of microsomal flavin-containing monooxygenase.

Prior administration of chlorpromazine (CPZ), imipramine (IMP), mercaptoethylamine (MEA), 1-(1-naphthyl)2-thiourea (ANTU) or phenyl-thiocarbamide (PTC) but not 1,4-dithio-1-threitol (DTT), was able effectively to prevent most of thioacetamide (TAC) -induced liver necrosis. These and previous observations suggest that liver microsomal flavin-containing monooxygenase critically controls the process of activation of TAC to the ultimate necrogen.

Acetamides↗

PubMed1983

Carbon tetrachloride-induced liver injury in the rabbit.

CCl4 administration to rabbits leads to early destruction of liver microsomal cytochrome P-450, to depression of glucose 6 phosphatase, to ultrastructurally revealable alterations and to an intense necrosis and fat accumulation in liver. Despite the known resistance of rabbit liver microsomes to lipid peroxidation, CCl4 administration to rabbits promoted lipid peroxidation of their liver microsomal lipids as revealable by the diene hyperconjugation technique, at periods of time from 1 to 12 h. Nevertheless, the intensity of this process is not equivalent to that occurring in rat liver microsomes, since the arachidonic acid content of rabbit liver microsomal lipids does not decrease at either 6 or 24 h after CCl4 administration. Rabbit liver is able to activate CCl4 to reactive metabolites that bind covalently to lipids. Relevance of covalent binding of CCl4 reactive metabolites and CCl4-promoted lipid peroxidation to CCl4-induced rabbit liver injury is analysed.

Animals↗

PubMed1983

Metabolism and activation of 1,1-dimethylhydrazine and methylhydrazine, two products of nitrosodimethylamine reductive biotransformation, in rats.

Nitrosodimethylamine (DMN) and two of its metabolites, methylhydrazine (MH) and 1,1-dimethylhydrazine (UDMH), were metabolized to CO2 by liver slices obtained from Sprague-Dawley rats. Under the conditions used, DMN and MH produced reactive metabolites that bound covalently to nucleic acids, but UDMH did not. Rat liver microsomes or 9,000 X g supernatants were able to transform DMN, MH, and UDMH to CH2O. In the cases of MH and UDMH, enzymatic and nonenzymatic pathways of CH2O formation were observed in both liver microsomes and 9,000 X g supernatants. DMN, MH, and UDMH led to covalent binding (CB) to proteins in incubation mixtures containing either microsomes or 9,000 X g supernatants. In the case of DMN, the process was enzymatic and required NADPH in both cellular fractions. In the case of MH, the process was enzymatic in microsomes and required NADPH and O2. With UDMH or MH and 9,000 X g supernatants, nonenzymatic interactions resulting in CB to proteins dominated. All these results suggest that part of the CO2 produced during DMN metabolism might be derived from UDMH and MH. Similarly, a significant part of the CB of DMN metabolites to proteins in incubation mixtures containing microsomes or 9,000 X g supernatants might be derived from enzymatic and nonenzymatic reactions of UDMH or MH. Also, a minor part of the CB of DMN-reactive metabolites to nucleic acids might have resulted from MH's further biotransformation to reactive metabolites. Overall, biotransformation of DMN and MH might not be a detoxication process, as previously thought, but one related to some of the DMN toxic effects.

Animals↗