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M Mourelle

Publications and source records attributed to M Mourelle.

72 records · Page 4Linked to original sources
PubMed1986

Cimetidine enhances and phenobarbital decreases parathion toxicity.

Parathion toxicity has been attributed to its metabolic product paraoxon which is formed in the mammal liver through the multiple oxidase enzymes. These are induced by barbiturates and inhibited by SKF 525 A and cimetidine. We assessed the effects of these drugs on the acute toxicity of parathion in rats by measuring the rate of survival at 24 h after the administration of the oral LD50 of parathion to four groups of rats: control and pretreated with the aforementioned drugs. Additional rats of these groups were used to measure the capability of liver isolated microsomes to transform p-nitroanisole to p-nitrophenol. In the control and cimetidine groups we also measured the transformation of parathion to paraoxon and p-nitrophenol by the liver microsomes. Phenobarbital increased the survival 100% whereas cimetidine and SKF 525 A dramatically potentiated parathion toxicity. Phenobarbital increased the formation of p-nitrophenol but cimetidine and SKF-525 A produced the opposite effect. Paraoxon and p-nitrophenol from parathion were decreased by cimetidine. Our results strongly suggest that parathion itself is largely responsible of its toxicity and the inhibition of its metabolism is harmful rather than beneficial.

Animals↗
PubMed1985

Thallium replaces potassium in activation of the (Na+,K+)-ATPase of rat liver plasma membranes.

The capacity of thallium to substitute for K+ in activation of (Na+,K+)-ATPase of liver plasma membranes was studied. Our results indicate that T1+ can replace K+ in the activation of the (Na+,K+)-ATPase of liver plasma membranes. In the presence of Na+, similar activation is obtained with T1+ concentrations only 1/10 of those of K+. In all other aspects, the (Na+,K+)- and (Na+,T1+)-ATPases were found to be identical.

Animals↗
PubMed1985

Adenosine triphosphatase activities in plasma liver membranes of rats treated with DDT and toxaphene.

The effect of exposure to chlorinated insecticides (DDT and toxaphene) on Na+,K+-ATPase, Mg2+-ATPase and Ca2+-ATPase activities of the plasma membrane of hepatocytes was determined. Acute treatment with DDT (200 mg per kg body weight) or toxaphene (110 mg per kg body weight) produced a significant decrease in Na+,K+-ATPase activity (80% and 85%, respectively) 24 h after treatment. DDT also produced a 30% decrease in Mg2+-ATPase and Ca2+-ATPase activity, but toxaphene treatment did not modify these enzymes. The effect of exposure to daily doses of DDT (30 mg per kg body weight) or toxaphene (16.5 mg per kg body weight) for a period of 3.5 months was also studied. Animals were sacrificed at 15-day intervals and results showed that Na+,K+-ATPase activity decreased 80% from the beginning of each treatment and the activity remained low throughout the treatment period. DDT, but not toxaphene, also led to a decrease in Mg2+-ATPase (20%) and Ca2+-ATPase (35%) activity. The low values observed from the beginning remained low throughout the treatment period. We believe that the general mechanism of ATPase inhibition by organochloride compounds could be the result of its interaction with membrane lipid components, although some differences could arise from differences in their spatial structure.

Adenosine Triphosphatases↗
PubMed1985

Cryptic adenosine triphosphatase activities in plasma membranes of CCl4-cirrhotic rats. Its modulation by changes in cholesterol/phospholipid ratios.

The activities of Na+,K+-, and Ca2+-ATPases were determined in plasma membranes obtained from livers of rats treated acutely and chronically with CCl4. Twenty-four hours after a single oral dose of CCl4 the ATPases decreased below 50% of control values. The activity of Ca2+-ATPase returned to normal after 4 days, and Na+,K+-ATPase activity returned to normal values after 12 days. One week after initiation of the chronic intraperitoneal treatment with CCl4, the Na,K+-ATPase decreased to 40% of control values and continued to decrease further until reaching values below 1%. Ca2+-ATPase followed a pattern similar to that obtained with Na+,K+-ATPase, except that the decrease was not as severe. Colchicine treatment prevented the modifications in ATPases when given simultaneously with CCl4 and reverted the alterations in ATPase activities of the CCl4-cirrhotic animals. Because ATPases are known to be modulated by the lipid composition of the membrane, we also determined the cholesterol to phospholipid ratio in all the isolated membranes. The ratios were increased in membranes with low ATPase activity due to an increase in the total concentration of cholesterol. Plasma membranes of cirrhotic rats treated with colchicine showed a low concentration of cholesterol, a decreased cholesterol to phospholipid ratio, and Na+,K+-ATPase activity was almost normal. When plasma membranes of cirrhotic rats were fused with phosphatidyl serine-containing liposomes, the cholesterol to phospholipid ratio decreased and the ATPase activity increased. The ATPase activity of normal plasma membranes decreased below 20% of control values when enriched with cholesterol. Our results suggest that the decrease in the plasma membrane Na+,K+-ATPase activity of the cirrhotic rat is due in part to an increase in its cholesterol concentration and in the cholesterol to phospholipid ratio.

Acute Disease↗
PubMed1984

Gamma-glutamyl transpeptidase: a sensitive marker in DDT and toxaphene exposure.

Gamma-glutamyl transpeptidase (GGTP) activity in rat liver plasma membrane and blood serum was investigated as an analytical marker for studying acute and sub-chronic exposure to DDT and toxaphene. Twenty-four hours after a single oral dose of DDT (200 mg per kg body weight) or toxaphene (110 mg per kg body weight), GGTP activity increased two-fold in liver plasma membranes, followed by a return to normal values 48 h post-exposure. In addition, serum GGTP activity doubled following acute exposure to DDT or toxaphene, and remained elevated for 48 and 96 h, respectively. Following 2 months continuous exposure to either insecticide, serum GGTP activity levels increased to double that of control values. GGTP activity in liver plasma membranes was elevated 2.5-fold following the initial treatment with toxaphene (16.5 mg per kg body weight per day) and the activity remained high throughout the treatment period (120 days). Prolonged exposure with DDT (30 mg per kg body weight per day) did not produce any change in liver GGTP activity. Based on these results, it appears that GGTP activity could be used as a marker for acute DDT and toxaphene exposure.

Animals↗
PubMed1984

Vitamin E improves membrane lipid alterations induced by CCl4 intoxication.

The effect of pretreatment with vitamin E on membrane lipid alterations produced by the acute intoxication with CCl4 was studied. Rats were treated with an oral dose of CCl4 (0.4 g per 100 g body weight) and 24 h later the animals were sacrificed and liver plasma membranes isolated. After extraction, the membrane lipids were analysed by thin-layer chromatography and quantitated by densitometry. The phospholipid: protein ratio determined in plasma membranes of CCl4-treated rats was almost three-fold higher than that found in control animals. Sphingomyelin (Sph) and phospharidyl choline (PC) increased, while phosphatidyl ethanolamine (PE) decreased in the plasma membranes isolated from the CCl4-treated group. Animals pretreated for 7 days with a daily dose of vitamin E (200 IU per kg body weight) showed a lower increase in the phospholipid: protein ratio (two-fold) and the changes in Sph, PC and PE were lower. When the rats were pretreated with a higher dose of vitamin E (400 IU per kg body weight) for the same period, the lipid composition of plasma membrane was normal. These results indicate that vitamin E can protect against the alterations induced by CCl4 on the liver membranes. The protective action of vitamin E against CCl4 membrane damage is probably associated with its antioxidant properties.

Animals↗
PubMed1983

Hormonal changes and adenylate cyclase system in rat bearing 7800 Morris hepatoma.

Adenylate cyclase activity was measured in plasma membranes isolated from Morris Hepatoma 7800 and from control and host livers. The only difference found in tumor enzyme activity was the lack of response to glucagon. The membrane-binding capacities for the pancreatic hormones insulin and glucagon were measured. Hepatoma membranes did not bind glucagon. Insulin-binding parameters could not be determined because of high non-specific binding. The plasma levels of insulin in the tumor-bearing animals were approximately half of those found in controls, whereas the glucagon levels in plasma were 50% higher in tumor-bearing animals. Thyroxine and triiodothyronine plasma levels were reduced in tumor-bearing rats, while the thyroid-stimulating hormone level was within normal limits. The amount of cAMP (275 pmol g-1) and cGMP (3.6 pmol g-1) in the tumor were lower than in the host and control livers, but the ratio of cGMP to cAMP in the tumor was increased by a factor of 2. These results are discussed with respect to control mechanisms of cell proliferation in comparison with other hepato-proliferative states.

Adenylyl Cyclases↗
PubMed1981

Changes in thyroid hormones following liver intoxication with carbon tetrachloride.

The metabolism of thyroid hormones was studied after carbon tetrachloride (CCl4) liver damage. Thyroxine (T4) and triiodothyronine (T3) levels fell and reached a nadir in the first 24 hours after CCl4 administration. Thyroxine binding globulins (TBG) and thyroid stimulating hormone (TSH) also decreased, reaching their lower values in the same period. Blood and liver T4 turnover measured in CCl4 treated rats were faster than in control animals. Therefore, at least three phenomena appear to be involved after CCl4 intoxication in rats: (1) increased utilization and turnover of thyroxine by the regenerating liver; (2) diminished thyroid hormone secretion by the thyroid gland, and (3) reduced concentration of serum iodothyronine carrier proteins. The results support the concept that the liver participates in the metabolic regulation of T3 and T4 which, in turn, control hepatocellular growth.

Animals↗
PubMed1981

Colchicine improves the alterations in the liver adenylate cyclase system of cirrhotic rats.

The adenylate cyclase system and the number and affinities of receptors for insulin and glucagon were studied in rats treated with CCl4 and in rats that received colchicine in addition to CCl4. Liver glycogen, cAMP and total collagen content were also measured in those animals. Rats received only mineral oil or only colchicine were used as controls. In this latter group, all parameters measured were normal. Differences in liver collagen content between groups treated with CCl4 and CCl4 + colchicine were not statistically significant. Basal adenylate cyclase activity was 2-fold increased in the CCl4 group. In the animals receiving CCl4 and colchicine, adenylate cyclase activity was normal. Adenylate cyclase activity stimulated by fluoride or by glucagon was also increased in the CCl4 group. However, this increase was due to to the enhanced basal activity. The number of receptors and the affinities of the receptors of glucagon and insulin were normal in all groups. cAMP levels were found increased in the CCl4 treated animals and this was accompanied by a 90% reduction in liver glycogen. In the group treated with CCl4 + colchicine, cAMP was normal and liver glycogen was only reduced 25%. These results suggest that part of the clinical and biochemical improvements observed in the colchicine treated animals were due in part to a reversal of the alterations of the adenylate cyclase system induced by CCl4.

Adenylyl Cyclases↗
PubMed1980

Some enzyme and hormonal attributes of hepatoma cell membranes.

Adenylate cyclase activity was measured in plasma membranes isolated form Morris Hepatomas (44 and 47C) and from their host livers. We found that the enzyme activity in the tumours was very low, approx. 5% of the level in control and host livers. The amount of cAMP and cGMP in the tumours was also lower than in the host livers but the ratio of cGMP to cAMP in the tumours was increased by a factor of 4-5. The membrane binding capacities for the pancreatic hormones insulin and glucagon were measured. Hepatoma membranes bound less glucagon than those of livers. A decrease in the number of the glucagon receptors was found but there were no changes in the affinity constant. For insulin, we found the same binding capacity as the host and control livers; thus there was an increase in the ratio of insulin bound/glucagon bound in tumours as compared to controls. The plasma levels of insulin in the tumour bearing animals were approximately half of those in control, whereas the glucagon levels in plasma were 60-62% higher in tumour bearing animals. These results are discussed in terms of the characterization of normal, foetal and regenerating liver, in comparison with slow growing hepatomas. The levels of cAMP and cGMP are discussed with respect to control mechanisms of cell proliferation.

Adenylyl Cyclases↗
PubMedDate not supplied

Abnormal matrix recognition by Morris hepatomas correlates with low glucagon binding capacity.

Liver biomatrix contains a group of connective tissue components needed for attachment, survival, and maintenance of liver-specific functions of adult rat hepatocytes in culture. An acidic extract of liver biomatrix that contains a group of glycoproteins can replace intact biomatrix in promoting attachment and survival of hepatocytes. However, except for albumin synthesis, liver-specific functions have not been tested. Acidic extracts of biomatrices prepared from heart, kidney, lung, and spleen (heterologous) contain a similar group of glycoproteins, but differ with respect to liver glycoproteins in their capacity to sustain hepatocyte binding. Normal hepatocytes attach poorly to heterologous glycoprotein extracts, although regenerating and tumoral hepatocytes attach to liver glycoproteins and adhere equally well or with greater efficiency to heterologous glycoprotein extracts. The increased efficiency of hepatocytes to attach to kidney biomatrix-derived glycoproteins showed a linear correlation with the decreased glucagon binding capacity of their isolated plasma membranes. An epithelioid cell-line derived from kidney (MDCK) attached with higher efficiency to kidney than to liver glycoproteins. These results suggest that biomatrices may contain specific glycoproteins needed for attachment and survival of their epithelial cells. This specificity is lost during the proliferative state of regenerating and tumoral hepatocytes and could be important in the general mechanism of tumor dissemination and metastases.

Animals↗
PubMedDate not supplied

Lack of glucagon receptors in Morris hepatoma 7800.

When compared to normal liver membranes, purified plasma membranes of regenerating liver and Morris hepatomas contain low but variable capacities to bind glucagon. This property is inversely related to the capacity of the isolated hepatocytes to bind to heterologous biomatrix glycoproteins. Since these parameters are characteristic of the proliferative state of the cells, it was important to further study the glucagon receptor protein and stimulation of adenylate cyclase activity. Our results show that 125I-iodinated plasma membranes obtained from normal liver contain three molecular species (117000, 98000, 86000 molecular weight) that can be eluted specifically with glucagon from a sepharose-glucagon affinity column. These proteins contain the putative glucagon receptor since binding of 125I- iodoglucagon is increased 150-fold as compared to unfractionated membranes. Plasma membranes obtained from Morris hepatoma (7800) and liver of chemically hepatectomized rats do not bind glucagon and lack these proteins. After inactivation with N-ethylmaleimide of the adenylate cyclase activity of the normal plasma membranes, they were fused with membrane of the hepatoma. The hybrid membranes showed 60% recovery of glucagon-stimulated cyclase activity. These results suggest that the plasma membranes of the proliferating liver cells do not contain receptor protein but have intact regulatory and catalytic subunits of the adenylate cyclase system.

Adenylyl Cyclases↗
PubMedDate not supplied

Cimetidine prevents and partially reverses CCl4-induced liver cirrhosis.

Liver injury produced by CCl4 depends on its metabolism by the liver cytochrome P450 enzyme system to a highly reactive intermediate (CCl3.). Cimetidine impairs cytochrome P450 and stimulates regenerative processes acting on DNA synthesis. This work was performed to investigate whether cimetidine may prevent CCl4-induced liver cirrhosis. Male Wistar rats were used: animals in group 1 received CCl4 (0.04 g per 100 g, i.p.) three times a week for 8 weeks; group 2 was treated with CCl4 plus cimetidine (120 mg kg-1, p.o.) three times a week for 8 weeks; group 3 received CCl4 for 8 weeks and then cimetidine for 4 weeks. Alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GTP) and alanine aminotransferase (ALT) activities, as well as protein and bilirubin, were measured in serum; collagen and lipoperoxidation were quantified in liver. Intoxication with CCl4 increased (P < 0.05) serum activities of alkaline phosphatase, gamma-GTP and ALT, and bilirubin concentration; liver collagen and lipoperoxidation were also increased. Cimetidine treatment prevented or reverted the increases in the three enzyme activities and in bilirubin content and the fall in proteins. It is worth noting that cimetidine co-treatment completely prevented both the increase in collagen content and the lipid peroxidation. The protective effect of cimetidine can be attributed to a reduction in cytochrome P450. However, it could also stimulate regenerative processes.

Alanine Transaminase↗
PubMedDate not supplied

Protective effect of colchicine on acute liver damage induced by CCl4. Role of cytochrome P-450.

The aim of this work was to study if colchicine protects against. CCl4-induced changes in hepatic biochemical parameters by reducing cytochrome P-450, by comparing the effects of colchicine and SKF 525-A, a well-known inhibitor of cytochrome P-450. Our results show that both drugs reduced the cytochrome P-450 content and p-nitroanisole o-demethylase activity to the same extent. However, colchicine afforded a total protection from markers of liver injury, while SKF 525-A protected only partially. The difference in the hepatoprotective activity of both drugs indicates that the beneficial effect of colchicine cannot be attributed solely to the inhibition of the activation of CCl4. Other actions, perhaps at the level of the propagation of lipid peroxidation or a 'membrane-stabilizing' effect cannot be ruled out.

Alanine Transaminase↗
PubMedDate not supplied

Inflammatory mediators and their influence on haemostasis.

Sepsis is the most important cause of mortality in the Intensive Care Units. At present, sepsis is understood to be the inflammatory response of the host to infection, rather than a direct effect of microbial aggression. From the clinical standpoint, this inflammatory response is known as systemic inflammatory response syndrome (SIRS). Pathophysiologically, SIRS is characterized by the activation of several groups of cell (monocytes/macrophages, PMNs, and endothelial cells) and by the release of inflammatory mediators (cytokines and others). Tumor necrosis factor (TNF) is the first cytokine released by endotoxin action over monocyte/macrophage. TNF secretion, modulated by interferon gamma (IFN gamma) and interleukin 10 (IL-10), is followed by release of other cytokines such as interleukins (IL) (IL-1, IL-6 and IL-8). These mediators are able to act over hemostasis activating the extrinsic pathway through tissue factor expression. The action of the mediators over endothelial cells induces an increase in plasminogen activator inhibitor type 1 (PAI-1) levels with inhibition of fibrinolysis. Both coagulation activation and fibrinolysis blockade result in fibrin deposit in the microvascular system. The complexity of the mechanisms implicated in systemic inflammatory response make a general rule so difficult to establish, because patient response is highly individualized and it is not possible to know which moment of this dynamic process is being analyzed.

Animals↗