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Biomedical subjects

J A Castro

Publications and source records attributed to J A Castro.

At least 109 records · Page 6Linked to original sources
PubMed1991

Blood groups in the Chueta community (Majorcan Jews).

A sample of 443 Chuetas (descendents of Majorcan Jews) was typed for the ABO, Rh, Lewis, Duffy, MNSs, Kell and P blood groups. Significant deviations from the Hardy-Weinberg equilibrium were observed in the MNSs and Duffy systems with a deficiency of heterozygotes. The gene frequencies were compared with those of the Balearic non-Jewish populations and significant differences were found. Genetic distances and cluster analysis demonstrated that the Chuetas resemble more their neighboring non-Jewish populations than other Jewish populations. Discriminant analyses showed that the Chuetas and other Jews considered in this study do not resemble each other but their host peoples with respect to these markers.

Alleles↗
PubMed1990

Ultrastructural effects of Nifurtimox on rat adrenal cortex related to reductive biotransformation.

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.

Adrenal Cortex↗
PubMed1990

Biotransformation of carbon tetrachloride and lipid peroxidation promotion by liver nuclear preparations from different animal species.

Liver nuclear preparations from male Syrian Golden hamster (SG); C3H mice and Sprague-Dawley (SD) rats were able to biotransform CCl4 to CHCl3. That ability was not NADPH dependent and proceeded to an equal extent under N2 or air. Studies in more detail with C3H mice preparations revealed that only one of the processes was of an enzymatic nature and that it was inhibited by 1 mM EDTA. There was a correlation between liver nuclear ability to biotransform CCl4 to CHCl3 in the species tested and their liver carcinogenic response to CCl4. That correlation was not observed when biotransformation was studied using liver slices instead of liver nuclei. Liver nuclear preparations from the 3 species were able to promote a lipid peroxidation (LP) process in the presence of CCl4. The process was fully NADPH dependent in the case of SG and SD preparations but not in C3H mice. Study of the process in detail in the case of C3H mice shows that in that case LP was heat and EDTA sensitive, particularly in the absence of NADPH. There was no correlation between the intensity of CCl4 promoted LP either in liver nuclear or liver slices preparations in the 3 species tested and their carcino genic response to CCl4. Results might suggest that LP does not determine or rate limit the process of cancer development by CCl4 but do not exclude its participation in a given stage of the overall process.

Animals↗
PubMed1990

Modulation of the course of CCl4-induced liver injury by the anti-calmodulin drug thioridazine.

Thioridazine (TDZ) administration to rats (50 mg/kg i.p.) 6 or 10 h after CCl4 treatment (1 ml/kg in olive oil i.p.) partially prevented necrogenic effects of this compound at 24 h but not at 72 h. TDZ did not have inhibitory effects on CCl4 activation, covalent binding (CB) of reactive metabolites to cellular constituents or CCl4-induced lipid peroxidation (LP). Moreover, TDZ had enhancing effects on both LP and CB. TDZ was able to increase protein and phospholipid synthesis and slightly but significantly enhanced protein but not phospholipid degradation in livers from control rats. TDZ administration decreased calcium liver content in CCl4-poisoned animals but did not change the intensity of CCl4-induced fatty liver. TDZ lowered body temperature in CCl4-treated animals during the 24 h observation period. These results and previous studies from our laboratory suggest calcium and calmodulin (CaM) participation in the CCl4 necrogenic effects on the liver but not in the hepatotoxin-induced fatty liver. TDZ-lowering effects on body temperature might also be a determinant in the delaying effects of this drug on the onset of CCl4-induced necrosis. Present experiments did allow discrimination between these two or other possible mechanisms for TDZ modulation effects.

Animals↗
PubMed1990

Red cell enzyme polymorphisms in the Balearic Islands. II. A comparison based on multivariate analyses.

A sample of 2143 individuals from Mallorca, coming from six geographic regions of this island: "Es Raiguer", "La Muntanya", "Es Plà", "Mijgorn", "Llevant" and "Palma", as well as 390 individuals from Eivissa island have been studied for the following six red cell enzyme systems: Esterase-D (ESD), acid phosphatase-1 (ACP1), glyoxalase-I (GLO1) 6-phosphogluconate dehydrogenase (PGD), phosphoglucomutase-1 (PGM1) and adenylate-kinase (AK1). The data were processed by means of multivariate statistical procedures: principal components, factorial correspondence and cluster analyses. The results indicate that ACP1 and ESD were the most suitable systems for the characterization of these caucasian populations, while GLO1 was important when different ethnic groups were included in the analyses. The Balearic gene frequencies fell within the European standard. Slight genetic distances were detected among the different Balearic populations, notably with the exception of the high differentiation of "La Muntanya".

Cluster Analysis↗
PubMed1990

Enzymatic polymorphisms in the Jewish community (Chuetas) from the Majorca Island.

The genetic polymorphism of four red cell enzymatic systems (ESD, ACP1, GLO1 and PGD) has been studied in the "Chueta" community (descendants of converted Jews from Majorca Island). The results have been compared with those of the population of Majorca that has no Jewish origin, and with other Jewish and non-Jewish Mediterranean populations. For these comparisons the following methods were used: chi 2 test, Wright's F, Nei's identities and distances and a dendrogram based on Nei's measures. The results obtained indicate that the Chueta community differs form the non-Chueta Majorcan population, although it resembles this non-Chueta population more closely than it does other Jewish ones.

Chi-Square Distribution↗
PubMed1989

Unmasking frequency-dependent selection in tri-cultures of Drosophila melanogaster.

Larval-to-adult viability was measured for three strains of Drosophila melanogaster: a wild strain and two eye colour mutant strains (cardinal and sepia) starting from seventy different genotypic compositions. Analyses of a sub-set of the data (not considering all genotypic frequencies) demonstrate frequency-dependence in the three strains. These results suggest that in this experiment, frequency-dependent selection may be masked by other selective forces, only being apparent when specific analyses are carried out.

Animals↗
PubMed1989

Late preventive effects against carbon tetrachloride-induced liver necrosis of the calcium chelating agent Calcion.

In agreement with the hypothesis that changes in calcium homeostasis might be significant in late stages of chemically-induced liver cell injury, a calcium chelating agent, Calcion, was able to partially prevent CCl4-induced liver necrosis observed at 24 h, when treatment was given as late as 6 or 10 h after the hepatotoxin. Calcion had minor or no effects on covalent binding of reactive metabolites to cellular components, or on lipid peroxidation or on CCl4 levels reaching the liver. Calcion treatment of CCl4-poisoned animals decreased CCl4-induced calcium increases in liver and increased glutathione levels decreased by hepatotoxin at 24 h. Calcion treatment was not able to prevent CCl4-induced fatty liver. Calcion protective effects were body temperature dependent but they were cancelled when Calcion-treated poisoned animals were kept normothermic. Results suggest that Calcion protective effects might be linked to calcium chelation or alternatively that they might derive from decreases in body temperature.

Animals↗
PubMed1989

Further studies on the mechanism of the late protective effects of phenylmethylsulfonyl fluoride on carbon tetrachloride-induced liver necrosis.

We previously reported that phenylmethylsulfonyl fluoride (PMSF) administration to rats (100 mg/kg, ip in olive oil) as late as 6 or 10 hr after CCl4 (1 ml/kg, ip as a 20% v/v solution in olive oil) can partially prevent the necrogenic response to the hepatotoxin at 24 hr. Here we confirm that observation by electron microscopy and provide further evidence that only in these circumstances were nuclear clumping of chromatin, slight dilatation of the endoplasmic reticulum, myelin figures and lipid droplets in the cytoplasm, large numbers of lysosomes and peroxisomes, glycogen, and slightly swollen mitochondria observable in the protected animals. A very minor part of the late protective effects of PMSF might be due to the effects of this drug on decreasing the intensity of covalent binding of CCl4-reactive metabolites or the intensity of CCl4-induced lipid peroxidation still occurring 6 or 10 hr after CCl4. PMSF administration did not prevent CCl4-induced decreases in cytochrome P450 content or glucose-6-phosphatase activity but partially prevented CCl4-induced calcium accumulation in liver. PMSF treatment increased glutathione and glycogen content in CCl4-poisoned animals, but did not markedly modify protein/phospholipid synthesis or degradation processes. Results suggest that the late protective effects of PMSF administration in CCl4-induced liver necrosis might be due to a favorable modulation of the calcium-calmodulin system similar to that previously described for other drugs.

Administration, Oral↗
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↗
PubMed1989

Carbon tetrachloride-induced liver cell injury in the Mongolian gerbil (Meriones unguiculatus).

1. Male Mongolian gerbils (Meriones unguiculatus) liver activates CCl4 to free radicals that bind covalently to cellular components (CB) and stimulate a lipid peroxidation (LP) process to a larger extent than the rat liver. 2. CCl4 administration results in a less intense necrogenic effect in gerbils than in rats and does not cause fatty liver. 3. CCl4 causes less intense effects on liver ultrastructure or calcium metabolism but more marked depression of glucose 6 phosphatase activity (G6P-ase) in gerbils than in rats. 4. Results suggest that a better ability of gerbil liver to keep calcium homeostasis than rat liver might be the cause of their relative resistance to necrosis. Higher intensity of CB and LP in gerbils than in rats might explain more intense effects on G6P-ase.

Aminopyrine N-Demethylase↗
PubMed1989

Species differences in the interaction between CCl4 reactive metabolites and liver DNA or nuclear protein fractions.

CCl4 has been reported to be a liver carcinogen for several mice strains, for Syrian Golden hamsters, but not for Sprague-Dawley rats. CCl4 is an experimental carcinogen for which no convincing evidence of mutagenicity is available despite the fact that CCl4 reactive metabolites bind covalently to liver DNA. Here we describe studies on the relationship between the intensities of the covalent binding (CB) of CCl4 reactive metabolites to liver DNA and nuclear proteins either in vivo or in vitro after activation to reactive metabolites by nuclear preparations, considering the known susceptibility of the C3H mice, Syrian Golden hamsters and Sprague-Dawley rats to CCl4. There was no correlation between the intensity of CCl4 carcinogenic effects on the liver and CB of CCl4 reactive metabolites to total DNA either in vitro or in vivo. A good correlation between carcinogenicity and CB to total nuclear proteins (in vivo or in vitro was found. Nuclear protein fractionation studies revealed CB of CCl4 reactive metabolites to both histone and non-histone proteins when nuclear preparations activated CCl4 either in the presence or absence of NADPH. Acidic and residual nuclear proteins were the favorite targets of the interaction with CCl4 reactive metabolites. A good correlation between CB to these nuclear protein fractions and CCl4 carcinogenicity in the three species was found.

Animals↗
PubMed1988

Nitrosodimethylamine metabolism in rat ovaries. Interactions of its metabolites with nucleic acids and proteins.

N-Nitrosodimethylamine (NDMA) was metabolized by ovarian slices of noninbred Sprague-Dawley rats (200-250 g body wt, to CO2 and to reactive metabolites that bind covalently to nucleic acids. That ability was about 10 or 5 times smaller than the one observed in liver slices, respectively. Both ovarian microsomes and mitochondria were able to biotransform NDMA to formaldehyde and to reactive metabolites that bind covalently to proteins. Formaldehyde formation by microsomes was significantly higher than that by ovarian mitochondria but of the same order of magnitude. Ability to lead to covalent binding to proteins in microsomes was not significantly different from that in the respective mitochondrial fraction. DNA isolated from ovarian slices activating NDMA revealed the presence of the altered bases 7-methylguanine (7-MeGua) and O6-methylguanine (O6-MeGua) resulting from NDMA reactive metabolites' attack. Results suggest potential, mutagenic, carcinogenic and reproductive risks derived from women's exposure to NDMA present in tobacco smoke, food, beverages, workplace or other environmental sources.

Animals↗
PubMed1988

Evidence for hydroxyl free radical formation during paraquat but not for nifurtimox liver microsomal biotransformation. A dimethyl-sulfoxide scavenging study.

The effect of several experimental conditions on methane (CH4) production from dimethylsulfoxide (DMSO) in incubation mixtures containing liver microsomes and NADPH generating systems was studied. The process was heat sensitive in part but a significant fraction was non-enzymatic in nature. CH4 formation from DMSO was not significantly modified by 2-diethylaminoethyl-2,2-diphenylvalerate. HC 1 (SKF 525A) or EDTA 1 mM and significantly enhanced under an atmosphere of (CO 80% + O2 20%) rather than under air. A marked increase in CH4 production was observed when paraquat (PQ) was included in incubation mixtures but not when nifurtimox (Nfx) was added. Results support the hypothesis of hydroxyl free radical (.OH) formation during PQ biotransformation but cast doubts about its production for the case of Nfx. The low temperature gas chromatographic separation of d3-CH4 from CH4 described opens the future possibility for detecting trace formation of .OH in vivo, without interference from fecal CH4 formation by administering d6-DMSO to animals and collecting exhaled gases produced, in chambers containing the entire animal.

Animals↗
PubMed1988

Further studies on the late preventive effects of the anticalmodulin trifluoperazine on carbon tetrachloride-induced liver necrosis.

Trifluoperazine (TFP) (50 mg/kg ip) administration to rats 6 or 10 hr after CCl4 (1 ml/kg ip in olive oil) significantly prevented liver necrosis but not fatty liver caused by the hepatotoxin at 24 hr as evidenced by either histology or electron microscopy. TFP given 6 hr after CCl4 significantly decreased the CCl4-induced increases in liver calcium content. TFP raised four to five times the liver glycogen content in control rats but was unable to modify decreased glycogen content of CCl4 poisoned animals. TFP administration increased phospholipid and protein synthesis as evidenced by studies on 32P incorporation into microsomal phospholipid and by experiments on [14C]leucine incorporation in microsomal protein fractions from control rat livers. No significant changes were observed in microsomal phospholipid degradation as studied by decay of label from 32P-prelabeled microsomal lipids or in increased protein degradation as evidenced by decay of label from [14C-guanidino]arginine-prelabeled microsomal proteins found in livers of control rats after TFP treatment. Electron microscopy observations of liver from control animals treated with TFP evidenced accumulation of glycogen in areas close to smooth endoplasmic reticulum (SER); large Golgi areas with an abundant number of lysosomes, and minor dilatation effects on the rough endoplasmic reticulum (RER) and nuclear membrane. Results suggest that TFP preventive effects might be due to the anticalmodulin actions of this drug.

Animals↗
PubMed1988

Studies on the mechanism of the acute and carcinogenic effects of N-nitrosodimethylamine on mink liver.

Outbreaks of liver necrosis and liver hemangiosarcoma were detected in a mink breeding colony in Argentina. Analysis of the Minks' food revealed the presence of 2.6 ppm dimethylnitrosamine (NDMA) in it, apparently as a result of the addition of nitrite as preservative. Previous studies gave evidence of the particular susceptibility of minks to NDMA and other hepatic insults. We have determined several biochemical parameters known to correlate with NDMA hepatotoxic effects and compared them with those in rat liver. NDMA administration to both species resulted in the formation of reactive metabolites able to interact with liver DNA to give N7-methylguanine and O6-methylguanine adducts. Biotransformation of NDMA by liver slices to CO2 was significantly lower in the mink than in the rat, whereas the covalent binding (CB) to nucleic acids was slightly lower than in in the rat. Aminopyrine N-demethylase activity was also significantly less in mink than in rat liver. The CB of NDMA reactive metabolites to microsomal proteins was not significantly lower in mink as compared to the rat, and the same holds true for the biotransformation of NDMA to formaldehyde by microsomal preparations. Results suggest that the high susceptibility of minks to NDMA might be partially due to a decreased ability to detoxicate NDMA but also to a higher intrinsic susceptibility of their liver cells to a given chemical insult.

Animals↗