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Biomedical subjects

J A Castro

Publications and source records attributed to J A Castro.

At least 163 records · Page 9Linked to original sources
PubMed1983

Studies on the mechanism of glutathione prevention of carbon tetrachloride-induced liver injury.

The prior administration of reduced glutathione (GSH) partially prevents carbon tetrachloride (CCl4)-induced liver necrosis observed at 24 h after administration of the hepatotoxin. No prevention occurs when observations are made at 72 h. GSH pretreatment does not significantly modify the intensity of the covalent binding of CCl4 reactive metabolites to microsomal lipids or the intensity of the CCl4-induced lipid peroxidation process at either 1, 3 or 6 h after poisoning. GSH administration does not significantly prevent CCl4-induced cytochrome P-450 destruction or glucose 6 phosphatase activity depression. Pretreatment with GSH does not significantly modify the levels of CCl4 or i.p. administered CCl4 reaching the liver at 1, 3 or 6 h after intoxication. Pretreatment with GSH significantly prevents CCl4-induced decreases in body temperature. Results are interpreted as suggesting that GSH prevents CCl4-induced liver necrosis by changing the liver cell's response to injury rather than by modification of early events of the process such as lipid peroxidation or covalent binding of reactive metabolites.

Animals↗
PubMed1983

[Effect of melatonin on L-leucine aminopeptidase in the hypothalamus and cerebral cortex of the normal and ovariectomized rat].

The effect of melatonin (500 micrograms/kg weight s.c. for 15 consecutive days) on the L-leucine amino peptidase (LAP) activity of the hypothalamus and brain cortex is studied on castrated and nan castrated rats. There was a significant increase in the LAP activity of hypothalamus (p less than 0.001 v.s. saline group) in the non castrated group, however, no changes were observed in the brain cortex. In the ovariectomized group injected from the 15th to 30th after castration, a very big decrease was recorded in the LAP activity in both the hypothalamus and brain cortex which was not modified by melatonin. This data is studied in relationship to the antigonadotrophic effect of melatonin on the non castrated animals since the changes of this activity in the hypothalamus are inversely related to the gonadotrophin secretion, specially luteinizing hormone.

Animals↗
PubMed1983

Tryptophan potentiation of the late cysteine preventive effects in carbon tetrachloride-induced necrosis.

Carbon tetrachloride (CCl4) (1 ml/kg/ip) induces a very intense necrotic effect on rat liver at 24 hr after administration. Cysteine (950 mg/kg/po) given 6 h after CCl4 exerted a very weak preventive effect on CCl4-induced necrosis, while tryptophan (300 mg/kg/po) did not. When both aminoacids are given together a very marked protective effect is observed. A possible participation of protein synthesis stimulation in the late protective effects of cysteine on CCl4-induced liver necrosis is discussed.

Animals↗
PubMed1983

Late preventive effects on dimethylnitrosamine, thioacetamide or galactosamine-induced liver necrosis of the inhibitor of proteases, phenylmethylsulfonyl fluoride.

Phenylmethylsulfonyl fluoride (PMSF) administration to rats, was effective in partially preventing liver necrosis induced by thioacetamide, dimethylnitrosamine or galactosamine, when given 6 hr after the hepatotoxins. In the case of galactosamine but not of the other necrogenic chemicals, protection was also observed when PMSF was given 10 hr after this compound. These results and previous studies from our laboratory suggest participation of protein degradation at late stages of liver injury by these chemicals.

Acetamides↗
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↗
PubMed1983

Prevention of carbon tetrachloride-induced liver necrosis by several amino acids.

Aspartic acid, cystine, methionine and tyrosine were protective against carbon tetrachloride (CCl4)-induced liver necrosis 24 h after its administration, when given 30 min before the hepatotoxin. Aspartic acid, cystine and tyrosine were also effective when given as late as 6 h after CCl4. The protective effects of these amino acids, however, were no longer evident when observations of CCl4-induced necrosis were made at 72 h, except for cystine, which retained its protective potential. Protective amino acid administration did not modify the concentration of CCl4 in liver, nor did it decrease the intensity of the covalent binding of CCl4 reactive metabolites to cellular constituents or the CCl4-induced lipid peroxidation. Consequently, protection cannot be attributed to modulation of these parameters. Cystine, tyrosine and aspartic acid significantly lowered body temperature of the CCl4-treated rats, while methionine did not. Combined, these results suggest that the protective effect is not attributable to lowering of body temperature in CCl4-treated animals. Protection probably results from changes in the cell response to injury promoted by amino acid administration.

Amino Acids↗
PubMed1982

Prevention of thioacetamide-induced liver necrosis by prior aminoacetonitrile or imidazole administration.

Prior administration of aminoacetonitrile (AAN) or imidazole but not isoxazole to rats, was able partially to prevent thioacetamide (TAC)-induced liver necrosis at 24 h. AAN and isoxazole did not prolong the pentobarbital sleeping time of the rats, while imidazole did. These and previous observations suggest a possible participation of non-cytochrome P-450 (P-450)-dependent aminoxidases in TAC activation to a necrogenic metabolite.

Acetamides↗
PubMed1982

Studies on the mechanism of alloxan-diabetes potentiation of carbon tetrachloride-induced liver necrosis.

Carbon tetrachloride (CCl4)-induced liver necrosis in alloxan diabetic rats is markedly more intense than in controls as established by determination of isocitric dehydrogenase activity in plasma or by histological techniques. The covalent binding (CB) of CCl4 reactive metabolites to liver microsomal lipids is higher in alloxan diabetic rats than in controls. Cytochrome c reductase activity remains unchanged in alloxan diabetic rats. All the alterations described above observed in the diabetic animals are reverted by insulin administration. CCl4-induced lipid peroxidation of microsomal lipids, in contrast, is equally intense in controls than in alloxan diabetic animals and it is not modified by insulin treatment. Body temperature in alloxan diabetic animals treated with CCl4 is lower than in controls treated with the hepatotoxin. Results suggest that part of the enhanced necrogenic response of the liver observed in alloxan diabetic rats is due to increased CB to liver cell constituents but available evidence from the present and another work suggest that increased susceptibility of the liver from alloxan diabetic animals play a major role in the potentiation of CCl4 deleterious effects.

Alloxan↗
PubMed1982

Chicken resistance to dimethylnitrosamine acute effects on the liver: a comparative study with other species.

Dimethylnitrosamine (DMN)-induced liver damage, as measured by the increase in plasma isocitrate dehydrogenase as well as by histologic assessment of necrosis, was marked after DMN ip administration (70 mg/kg) in males of all noninbred species tested (BALB/c mouse, Sprague-Dawley rat, Syrian golden hamster, general purpose guinea pig) but not in the noninbred White Leghorn chicken. At 1 and 3 hours after DMN injection, liver DMN levels were not lower in the chicken as compared to levels in the other species. Furthermore, in all species except the chicken, significant decreases were found at 3 hours as compared to 1 hour after DMN administration. DMN metabolism to CO2 and to formaldehyde, as well as covalent binding of DMN-reactive metabolites to either proteins or nucleic acid, was measured with the use of liver slices, microsomes, and/or 9,000 X g supernatants. Results indicated that chicken liver had a very low capacity for metabolism and activation (29-3,166 times lower than comparable data in mice or hamsters).

Animals↗
PubMed1982

Effect of 3 amino 1,2,4 triazole administration on the early CCl4-induced ultrastructural alterations in rat liver.

CCl4 administration to rats caused at 3 and 6 h intense effects on the liver-cell endoplasmic reticulum such as dilatation, disorganization, detachment of ribosomes, development of extensive areas of smooth component (SER) and formation of myelin figures. 3 Amino 1,2,4 triazole administration (AT) at 3 and 6 h led to the formation of round small vesicles from the rough endoplasmic reticulum (RER), detachment of ribosomes, appearance of extensive areas of SER, appearance of elongated and distorted mitochondria with an increase in the number of peroxisomes. The administration of CCl4 to AT-pretreated animals led to a mutual cancellation of the effects on the RER, particularly remarkable at 3 h but still evident at 6 h; also, the formation of myelin figures was prevented. The other effects on cell ultrastructure exerted either by CCl4 or by AT were also observed with the combination of both chemicals. These observations reinforce the hypothesis about the need of either covalent binding of CCl4 metabolites to cellular constituents or lipid peroxidation, or both, in the origin of CCl4-induced alterations.

Amitrole↗
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↗
PubMed1981

Further studies on dimethylnitrosamine metabolism, activation and its ability to cause liver injury.

Effects were studied of aminoacetonitrile (AAN), dibenamine (DB) diethyldithiocarbamate (DDTC) dimethylformamide (DMF), disulfiram (DS), and 2-mercapto-1-methylimidazole (MMI) on the in vitro dimethylnitrosamine (DMN) metabolism to CO2, covalent binding (CB) of DMN metabolites to nucleic acids in liver slices, DMN demethylase (DMNase) in male rat liver microsomes or 9,000 g supernatants and CB to microsome of 9,000 g supernatant proteins. Effects of those chemicals on DMN-induced rat liver necrosis were also studied, except for DS whose preventive effect was previously reported by our laboratory. All the chemicals significantly prevented DMN-induced liver necrosis, except for MMI that had no effect. All these compounds when added to incubation mixtures containing liver slices from Sprague-Dawley rats, significantly inhibited transformation of DMN to CO2 and CB to nucleic acids and when they were injected into animals and liver slices prepared afterwards, they did so except for MMI and DMF that had no effect. None of the chemicals tested except DDTC and MMI modified CB to microsome proteins whereas the CB to 9,000 g supernatant proteins was significantly decreased by all the chemicals except MMI. DMNase activity either in microsomes or 9,000 g supernatants was significantly inhibited by all the compounds except MMI.

Animals↗
PubMed1981

Effects of repeated administration of rat 2-diethylaminoethyl-2-2-diphenylvalerate-HCI (SKF 525 A) on liver.

Repetitive administration to male rats of 2-diethylaminoethyl-2-2-diphenyl-valerate-HCI (SKF 525 A) (50 mg/kg, i.p.), decreases the intensity of [14C]-orotic acid incorporation/mg of RNA but not the 14C-incorporation/g liver. The RNA content/g liver is significantly higher in SKF-treated animals than in controls. Decay of label in liver RNA from [14C] orotic acid pretreated animals, is not significantly different in SKF 525 A treated animals than in controls. SKF 525 A repetitive administration, does not modify the rate of incorporation of 32P in liver microsomal lipid when results are expressed per microgram of inorganic phosphorus but it does when expressed in terms of per gram liver. There is a significant decrease in the decay rate of label from 32P-prelabeled liver microsomal phospholipids when animals are treated with SKF 525 A. There is a significant increase in the protein and phospholipid content in the smooth endoplasmic reticulum fraction. The electron microscopy of liver from SKF 525 A-treated animals, shows the presence of large areas of round vesicles of swollen endoplasmic reticulum, partly due to smooth component and part due to rough component, having detached the ribosomes from their membranes. Results suggest an inhibitory effect of SKF 525 A on RNA and phospholipid degradative processes.

Animals↗
PubMed1981

Effects of cysteine and cystamine on the carbon tetrachloride induced decrease in arachidonic acid content of rat liver microsomal phospholipids.

Cystamine and cysteine inhibited the carbon tetrachloride (CCl4) prooxidant effect on rat liver microsomal preparations, at concentrations ranging from 0.001 mM to 1 mM. Cysteine exhibited a biphasic effect being an inhibitor of the prooxidant action at concentrations below 0.1 mM and acting as an enhancer at 1 mM. Cystamine but not cysteine pretreatment of the rats prevented the CCl4 induced decrease in the arachidonic acid content of liver microsomal phospholipids. However, both cystamine and cysteine led to decreases in arachidonic acid similar to that produced by CCl4 but they do not have deleterious effects on the liver. These results cast doubt on the role of lipid peroxidation in the liver cell injury by CCl4.

Animals↗
PubMed1981

Enhancement of the dimethylnitrosamine acute effects in rat liver by prior treatment with triton WR-1339.

Prior administration of Triton WR-1339 (tyloxapol, an anionic surfactant) to noninbred Sprague-Dawley male rats significantly enhanced the intensity of the necrogenic effect of dimethylnitrosamine (DMN) on the liver. This phenomenon was established by determination of NADP+-linked isocitrate dehydrogenase activity in the plasma and by histologic procedures. This enhancing effect was not due to an increase in the levels of DMN that reached the liver, because the content of DMN in the livers of Triton WR-1339-treated or untreated animals at 1 or 3 hours was not significantly different. Triton WR-1339 administration had no effect on DMN liver metabolism to formaldehyde or CO2; in addition, the covalent binding of DMN metabolites to nucleic acids or proteins was not modified by pretreatment with Triton WR-1339. However, in vitro, high concentrations (1 mg/ml) of Triton WR-1339 decreased the intensity of these parameters. This effect disappeared when the concentration was lowered to 0.4 mg/ml. Results are compatible with the hypothesis that the potentiating effects of Triton WR-1339 on liver damage caused by DMN and other hepatotoxins were due to a modification of the response of liver cells to injury.

Animals↗
PubMed1981

Liver microsomal drug-metabolizing enzyme activity: enhancement by blockade of degradative processes in promethazine-treated rats.

Daily injection of promethazine over 4 days significantly increased the liver cytochrome P-450 content and ethyl morphine N-demethylase activity. These increases were evident after the first dose and were prevented by puromycin or actinomycin D administration. Repeated administration of promethazine does not increase the liver's ability to incorporate [14]C DL-leucine in microsomes but slows down the decay of radioactivity in microsomes previously labelled with ([14C]-guanidino) arginine. Repeated treatment with promethazine leads to a marked proliferation of the rough endoplasmic reticulum (RER) and a slight increase in the smooth endoplasmic reticulum (SER). Our findings suggest that the enhancement of P-450 and EM-ase activity result from the decelerating effect of promethazine on protein degradation.

Animals↗