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Biomedical subjects

A Wendel

Publications and source records attributed to A Wendel.

At least 145 records · Page 8Linked to original sources
PubMed1983

Non-reactivity of the selenoenzyme glutathione peroxidase with enzymatically hydroperoxidized phospholipids.

Selenium-containing glutathione peroxidase (EC 1.11.1.9) was purified 6000-fold from bovine red blood cells to apparent homogeneity. Lipoxygenase (EC 1.13.11.12) was enriched 20-fold from soybean acetone powder. Linoleic acid was peroxidized with lipoxygenase and then used as a substrate in the glutathione peroxidase reaction. Analogous experiments were conducted with synthetic 1,2-dilinoleoyl-L-alpha-glycerophosphocholine and with natural bovine heart cardiolipin. The peroxidized phospholipids were reactive with glutathione peroxidase only after enzymatic attack by phospholipase A2 (EC 3.1.1.4). This result implies that the membrane-protective function of glutathione peroxidase includes preceeding phospholipase action and excludes a direct interaction of this enzyme with membrane-bound lipid hydroperoxides.

Animals↗
PubMed1983

Drug-induced lipid peroxidation in mice--V. Ethane production and glutathione release in the isolated liver upon perfusion with acetaminophen.

Isolated liver from phenobarbital-induced male mice was perfused using infusions of cytochrome c pulses as quality control of the system. Livers spontaneously evolved 1.1 pmoles ethane g-1 liver min-1, exogenous pentane disappeared with 0.6 pmoles g-1 min-1. Infusion of 0.26 mmoles/l. FeCl2 led to immediate ethane production followed later on by lactate dehydrogenase release from the liver. Infusion of acetaminophen resulted in hepatic ethane production at drug concentrations greater than 0.1 mmoles/l. A maximum effect was observed at 2 mmoles/l. of acetaminophen infused while higher concentrations, up to 10 mmoles/l. delayed ethane release although they enhanced the rate of glutathione depletion. This glutathione efflux decreased from 12 nmoles/g-1 min-1 observed after perfusion of medium alone to 2.9 nmoles/g-1 min-1 when AAP was infused. The slope of the pseudo first order depletion kinetics depended on the acetaminophen concentrations. This glutathione release represents the perisinusoidal portion of the total efflux measured here independently from the biliary secretion. The results show that in agreement with the in vivo findings acute intoxication of liver with high doses of this drug lead to lipid peroxidation, while in vitro an apparent antioxidative effect was measured. The implications for drug screening are probably important.

Acetaminophen↗
PubMed1983

The influence of selenium intake on chronic adriamycin toxicity and lipid peroxidation in rats.

This paper reports on the influence of selenium intake on antioxidant protective systems during chronic adriamycin (AM) treatment in rats. Rats were kept for 14 weeks on a selenium deficient (Se-) diet or a diet containing selenium (Se+). No significant differences were found in any group with regard to the cardiac content of total and reduced glutathione (GSH) and heart superoxide dismutase specific activity. AM treatment did not modify lipid peroxidation as measured by cardiac malondialdehyde (MDH) formation in rats receiving either the Se- or the Se+ diet. In the Se+ rats AM had no effect on the exhalation of ethane or pentane but decreased the exhalation of ethane and increased that of pentane in the SE- rats. In Se- AM-treated rats mortality was higher. Since this did not seem to be correlated with modifications of any of the biochemical parameters taken into consideration, it is suggested that the better resistance of Se+ animals to AM treatment is related to some factors not yet identified.

Animals↗
PubMed1983

Hepatic lipid peroxidation: caused by acute drug intoxication, prevented by liposomal glutathione.

Acute intoxication of mice with high doses of paracetamol (acetaminophen, 4-hydroxyacetanilide) led to a dose-dependent lipid peroxidation (LPO) measured in vivo by ethane exhalation and in vitro by malondialdehyde formation and glutathione depletion. Induction of microsomal enzymes enhanced LPO, inhibition of the monooxygenase systems totally suppressed it. Other drugs activated in phase I, i.e., furosemide, ethylmorphine or aminopyrine acted similarly if the phase II conjugation to glutathione was paralysed by glutathione depletion with diethylmaleate. The concept of lipid peroxidation being an early causal event in hepatocellular destruction was further examined experimentally: 1) Animals with alimentary selenium deficiency lacking liver selenium-dependent glutathione peroxidase activity were much more susceptible to paracetamol-induced liver necrosis and LPO. 2) Normally fed animals were totally resistant when pretreated by intravenous liposomally entrapped glutathione. Administration of free glutathione led to a similar increase in hepatic glutathione content but the animals were much less protected. 3) Isolated perfused mouse liver released quantitatively similar amounts of ethane upon perfusion of paracetamol. The hydrocarbon evolution was reversible and preceded cell disintegration monitored by release of lactate dehydrogenase. 4) The few human data available indicate that man has a much lower activity of hydroperoxide metabolizing enzymes and much less glutathione. The results suggest an involvement of lipid peroxidation in acute chemical primary lesions. A general pathogenic mechanism for liver injury cannot be derived at present from the data available.

Acetaminophen↗
PubMed1982

Drug-induced lipid peroxidation in mice--II. Protection against paracetamol-induced liver necrosis by intravenous liposomally entrapped glutathione.

If injected intravenously 2 hr before the drug, a dose of more than 175 mg/kg body weight glutathione (0.57 mmol/kg) protected male mice from acute liver necrosis induced by intraperitoneal administration of 400 mg/kg (2.65 mmol/kg) paracetamol. Soluble glutathione yielded a limited, and liposomally entrapped glutathione an optimal dose-dependent protective effect against drug-induced lipid peroxidation (as measured by in vivo ethane exhalation) liver necrosis (assessed by serum transaminases) and hepatic glutathione depletion (determined post mortem). N-Acetylcysteine solution had no effect in this model.

Acetaminophen↗
PubMed1982

Drug-induced lipid peroxidation in mice--III. Glutathione content of liver, kidney and spleen after intravenous administration of free and liposomally entrapped glutathione.

The half-life of extracellular glutathione was found to be 1.9 min in fed mice with a hepatic glutathione content of 44 +/- 10 nmol glutathione per mg protein. It was 4.9 min in animals that had been fed for 48 hr a liquid sucrose diet resulting in a decreased hepatic glutathione of 25 +/- 7 nmol/mg. A single intravenous injection of 16.2 mumol liposomally entrapped glutathione led to an increase in hepatic glutathione to 45 nmol/mg in the sucrose-fed mice after 2 hr and had no effect in the fed group. The spleen glutathione content reached a maximum at 30 min after injection in both groups. The maximum uptake into liver was 21% of the applied dose, into the spleen 7% and into the kidneys 2.4%. Injection of glutathione in solution led to a similar increase of hepatic glutathione as observed with GSH-containing liposomes, while liposomes filled with the constituent amino acids had only a marginal effect. The spleen took up only liposomal GSH. In contrast, the kidney glutathione content increased within 10 min up to 150% upon injection of free glutathione. The findings are consistent with a rapid hydrolysis of extracellular free glutathione followed by an interorgan turnover utilizing the constituent amino acids for resynthesis in the liver. Pretreatment of the animals with the glutathione synthesis inhibitor buthionine sulfoximine essentially abolished the hepatic glutathione increase upon treatment with GSH-liposomes or with the free compound. The finding that only liposomally entrapped glutathione protects mice against liver necrosis induced by highly dosed paracetamol is discussed with respect to differential uptake and distribution of GSH-liposomes in the liver.

Animals↗
PubMed1982

[Activity of the glutathione redox system in human erythrocytes at various ages].

Human erythrocytes were separated into three groups according to their density and age by centrifugation in a continuous Percoll gradient. The specific activities of glucose-6-phosphate dehydrogenase, catalase, glutathione peroxidase, glutathione reductases as well as the glutathione and selenium content were highest in the youngest cell and uniformly decreased by about 20-30% in the eldest group. The age-dependence of superoxide dismutase was much more pronounced. The malondialdehyde content taken as an estimate for lipid peroxidation showed an inverse age dependence and increased by 35% in the eldest cell population. Red blood cells from 10 anemic patients exhibited less glutathione and also less malondialdehyde, while GSH-peroxidase and GSSG-reductase contents were higher. The parameters showed similar age profiles as in healthy subjects. The findings support the concept of lipid peroxidation as one of the causal events in red cell aging, but do not allow to deduce the involvement of a single enzyme related to the glutathione redox cycle in this process.

Adult↗
PubMed1982

Chemically-induced glutathione depletion and lipid peroxidation.

Malondialdehyde (MDA) formation in mouse liver homogenates was measured in the presence of various glutathione depletors (5 mmol/l). After a lag phase of 90 min, the MDA formation increased from 1.25 nmol/mg protein to 14.5 nmol/mg in the presence of diethyl maleate (DEM), to 10.5 with diethyl fumarate (DEF) and to 4 with cyclohexenon by 150 min. It remained at 1.25 nmol/mg with phorone and in the control. On the other hand, glutathione (GSH) dropped from 55 nmol/mg to 50 nmol/mg in the control to, less than 1 with DEM, to 46 with DEF, to 3 with cyclohexenon and to 7 with phorone. The data show that the potency to deplete GSH is not related to MDA production in this system. DEM stimulated in vitro ethane evolution in a concentration-dependent manner and was strongly inhibited by SKF 525A. From type I binding spectra to microsomal pigments the following spectroscopic binding constants were determined: 2.5 mmol/l for phorone, 1.2 mmol/l for cyclohexenon, 0.5 mmol/l for DEM and 0.3 mmol/l for DEF. In isolated mouse liver microsomes NADPH-cytochrome P-450 reductase and NADH-cytochrome b5 reductase activity were unaffected by the presence of DEM, whereas ethoxycoumarin dealkylation was inhibited. Following in vivo pretreatment, hepatic microsomal electron flow as determined in vitro was augmented in the presence of depleting as well as non-depleting agents, accompanied by a shift from O2- to H2O2 production. It is concluded that it is not the absence of GSH which causes lipid peroxidation after chemically-induced GSH depletion but rather the interaction of the chemicals with the microsomal monoxygenase system.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1981

Binding of paracetamol metabolites to mouse liver glutathione S-transferases.

In mouse liver homogenate with an intact microsomal metabolism covalent binding of [14C]-paracetamol amounted to 1 nmol/mg protein. 65% of the total radioactivity were bound to soluble protein and 35% to microsomes. In the soluble fraction the major radioactivity peak co-chromatographed with glutathione S-transferase activity on Sephacryl S-300. Two different minor labelled fractions with apparent molecular weights of 130 000 and 25 000 daltons were also found. In a second experiment in a reconstituted system of microsomes and supernatant, 86% of the radio-activity was bound to supernatant and 14% by of microsomes. Following ion exchange chromatography of the supernatant on DEAE-Sepharose, the two major radioactivity-containing fractions coincided with GSH-S-transferase activities, but not with selenium-dependent or non-selenium-dependent glutathione peroxidase. The data show that irreversible binding of paracetamol metabolites in mouse liver occurs preferentially to GSH-S-transferases.

Acetaminophen↗
PubMed1980

The activity of the peroxide-metabolizing system in human colon carcinoma.

The major parameters of the peroxide-metabolizing system were investigated in eight human colon carcinoma excisions and compared with apparently non-neoplastic colon tissue from the same patients. The mean malondialdehyde level as an index of lipid peroxidation was 147 pmol/mg protein in carcinoma compared to 40 pmol/mg in healthy tissue. The following relations of specific activities in carcinoma and healthy tissue were found: superoxide dismutase 3.9 micrograms/mg protein (carcinoma): 2.4 micrograms/mg (healthy), glutathione peroxidase 23 mU/mg:10 mU/mg; GSH-transferase 38 mU/mg:25 mU/mg; catalase 2.3 mK/mg:4.1 mK/mg. The mean selenium concentration in carcinoma was 36 ng/mg protein compared to 24 ng/mg. The difference between carcinoma and normal tissue showed an overall-significance of p < 0.002 for the whole set of data. No significant differences were found in GSH levels (12.6 nmol/mg protein in carcinoma: 9.4 nmol/mg in normal colon), GSSG levels (0.6 nmol/mg:0.7 nmol/mg) and in the protein content (70 +/- 23.5 mg/g wet tissue: 66 +/- 20 mg/g). It is concluded that the enhanced lipid peroxidation in tumor tissue may be due to peroxisomally generated H2O2 in conjunction with a lowered catalase activity.

Adenocarcinoma↗