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O Strubelt

Publications and source records attributed to O Strubelt.

At least 19 recordsLinked to original sources
PubMed1992

The toxicological relevance of paracetamol-induced inhibition of hepatic respiration and ATP depletion.

In order to elucidate the role of mitochondrial dysfunction in paracetamol-induced hepatotoxicity, the effects of paracetamol on the oxygen consumption and ATP content of the isolated perfused rat liver were correlated with parameters of hepatic viability and hepatotoxicity. Paracetamol at 5 g/L reduced the oxygen consumption of the livers by about 80% and hepatic ATP content by 96%. Hepatotoxicity was evident from the nearly complete interruption of bile secretion, a marked release of enzymes [glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH)] in the perfusate, a depletion of hepatic glutathione and an accumulation of calcium in the liver. Paracetamol-induced hepatotoxicity could be prevented completely by using livers from non-fasted rats as well as by addition of fructose to the perfusate of livers from fasted animals. Both treatments resulted in an increased energy supply from anaerobic glycolysis as evidenced by a large release of lactate and pyruvate into the perfusate, but did not inhibit paracetamol-induced decline of oxygen consumption. The decrease in hepatic oxygen consumption depended on the dose of paracetamol and occurred first at a concentration of 0.2 g/L (-10%). LDH and GPT release, on the other hand, was elevated at 2 and 5 g/L and calcium accumulation occurred at 5 g/L paracetamol only. Inhibition of mixed-function oxidases by dithiocarb did not prevent the decrease in oxygen consumption and the resulting hepatic injury induced by paracetamol. The oral administration of the high dose of 5 g/kg paracetamol in vivo to rats exerted strong hepatotoxicity but produced maximal serum levels of 800 mg/L paracetamol only and did not decrease hepatic oxygen consumption as measured in vitro. Our results show that in the isolated perfused rat liver in vitro, only high concentrations of paracetamol can produce "chemical hypoxia" by attacking mitochondria so as to cause hepatic injury. Such high concentrations of paracetamol are not attained in vivo, however. "Chemical hypoxia", thus, seems not to be relevant to the well-known hepatotoxic action of paracetamol.

Acetaminophen↗
PubMed1992

Effect of antioxidants on hypoxia/reoxygenation-induced injury in isolated perfused rat liver.

Isolated perfused livers from rats fasted overnight were subjected to 30 min. of hypoxia followed by reoxygenation for 60 min., resulting in marked cytotoxicity as evidenced by an enhanced release of cytosolic enzymes (lactate dehydrogenase: 14-fold over controls, glutamate-pyruvate-transaminase: 12-fold over controls) and glutathione (twofold over controls) into the perfusate, by calcium accumulation (by a factor of 1.4) in the tissue and by an 80% inhibition of bile secretion. Virtually no mitochondrial injury became apparent and no evidence for lipid peroxidation could be found. In the presence of ascorbate, an augmentation of hepatic injury was observed. This might be due to the pro-oxidant activity of ascorbate in the presence of ionized iron, which is easily released from high molecular weight stores under reductive (e.g. hypoxic) conditions. The water soluble vitamin E analogue trolox C as well as propyl gallate clearly protected the liver against hypoxia/reoxygenation injury, yielding further evidence for a causative role of oxidative stress in this model. Due to their water solubility and their high efficacy as free radical scavengers, these antioxidants might be of therapeutic value.

Animals↗
PubMed1991

Vanadate-induced toxicity towards isolated perfused rat livers: the role of lipid peroxidation.

The toxic potential of sodium orthovanadate towards isolated perfused rat livers was investigated at a dose of 2 mmol/l. In livers from fasted rats, vanadate led to a release of cytosolic (glutamate-pyruvate-transaminase (GPT) and lactate dehydrogenase (LDH] and mitochondrial (glutamate dehydrogenase (GLDH] enzymes, an accumulation of calcium in the liver, a marked depletion of hepatic glutathione and an enhanced release of it into the perfusate, as well as an augmented formation and release of thiobarbituric acid-reactive material by the liver. Furthermore, a marked inhibition of oxygen consumption was observed. Vanadate-induced vasoconstriction resulted in a progressive decrease in perfusate flow rate. Control experiments with similarly reduced flow rates led to a comparable reduction in oxygen consumption. GPT and LDH release and hepatic glutathione depletion were also evident, though to a lesser extent than in the presence of vanadate, but no increase in GLDH release, in tissue calcium content or TBA-reactive material in the liver or the perfusate were observed. Thus, indirect toxic effects due to a reduced flow rate contribute only partly to vanadate hepatotoxicity and do not affect mitochondrial integrity. Omission of calcium from the perfusate did not prevent hepatotoxic responses to vanadate, although less calcium was present in the treated livers than in the control organs, indicating that calcium influx is not involved in vanadate-induced hepatotoxicity in the intact organ, in contrast to isolated hepatocytes. Feeding the animals, resulting in an activation of anaerobic energy conservation reactions, strongly attenuated vanadate hepatotoxicity indicating that the energetic status of the liver is the main target of vanadate. Superoxide dismutase did not affect the hepatotoxic responses of livers from fasted rats towards vanadate, while allopurinol and deferrioxamine inhibited lipid peroxidation and hepatotoxicity due to vanadate. The strong correlation between induction of lipid peroxidation and hepatotoxicity and the inhibition of both processes in parallel by antioxidants are suggestive of a causative role for lipid peroxidation in vanadate-induced hepatotoxicity.

Alanine Transaminase↗
PubMed1991

Effect of antioxidants on vanadate-induced toxicity towards isolated perfused rat livers.

The effect of trolox C, a water soluble vitamin E analogue, propyl gallate and ascorbate on vanadate hepatotoxicity was investigated in vitro. In isolated perfused livers from fasted rats, sodium orthovanadate (2 mmol/l) led to toxic responses including reduction of oxygen consumption, release of cytosolic (glutamate-pyruvate-transaminase (GPT) and lactate dehydrogenase (LDH)) and mitochondrial (glutamate-dehydrogenase (GLDH)) enzymes, intracellular accumulation of calcium, a marked depletion of glutathione (GSH) and an enhanced formation and release of thiobarbituric acid- (TBA) reactive material. Trolox C and propyl gallate inhibited the release of GPT and LDH partially and that of GLDH totally, but had no influence on vanadate-induced calcium accumulation or on the reduction of oxygen consumption. Both agents suppressed vanadate-induced lipid peroxidation (LPO) and partially prevented GSH depletion. Ascorbate failed to provide any protection probably due to the interference of its pro-oxidant potential with its antioxidant activity. The protection, mainly of mitochondria, afforded by those agents which also inhibited LPO substantiates our previous findings that the pro-oxidant activity of vanadate is mainly responsible for its direct hepatotoxic actions [2]. Besides, reduction of organ perfusion rate due to vasoconstriction also contributes to vanadate toxicity, but oxidative stress is not involved in this indirect toxic activity.

Alanine Transaminase↗
PubMed1990

[Acute kidney failure during psoriasis therapy with fumaric acid derivatives].

24 days after starting treatment of psoriasis with fumaric acid derivatives (0.8-1.0 g orally, plus unknown quantities locally) a 21-year-old woman developed acute oliguric renal failure with a rise of serum creatinine levels to 1094 mumol/l (12.4 mg/dl). Deterioration of renal function had been preceded by severe abdominal symptoms with nausea, vomiting and colicky pain. On admission to hospital she was dehydrated with hyponatraemia and hypokalaemia. There was glomerular microhaematuria, increased excretion of renal epithelia, and tubular proteinuria. Renal biopsy demonstrated acute tubular damage with vacuolization of proximal epithelia, dilated tubules and scattered necroses. After intermittent haemodialysis (13 courses over two weeks) renal function gradually recovered, as demonstrated at a follow-up examination four months after discharge.

Acute Kidney Injury↗
PubMed1990

The role of iron and glutathione in t-butyl hydroperoxide-induced damage towards isolated perfused rat livers.

The hepatotoxic and lipid peroxidative potentials of t-butyl hydroperoxide (t-BuOOH) towards isolated perfused rat livers were investigated at doses of 1 and 3 mmol l-1. t-BuOOH led to a concentration-dependent release of cytosolic (glutamate-pyruvate transaminase and lactate dehydrogenase) and mitochondrial (glutamate dehydrogenase) enzymes, an accumulation of calcium in the liver, a marked depletion of hepatic glutathione and an enhanced release of it into the perfusate, as well as an enhanced formation and release of malondialdehyde (MDA) by the liver. These effects were blocked in the presence of the potent iron chelator deferrioxamine, and enhanced in livers from iron-overloaded as well as in livers from glutathione-depleted rats. Our results indicate that the hepatotoxic and pro-oxidant actions of organic hydroperoxides depend upon the presence of ionized iron as a catalyst of radical-forming breakdown reactions, and are potentiated by impairment of glutathione-dependent detoxification reactions.

Alanine Transaminase↗
PubMed1990

Protection by exogenous glutathione against hypoxic and cyanide-induced damage to isolated perfused rat livers.

In experiments with isolated perfused livers from fasted rats, addition of 2 mmol/l glutathione (GSH) to the perfusion medium protected against hepatic damage induced by cyanide or hypoxia and reoxygenation as evidenced by leakage of lactate dehydrogenase and hepatic calcium accumulation. In control experiments as well as in experiments with cyanide or hypoxia and reoxygenation, exogenous glutathione resulted in an augmentation of cellular glutathione content, indicating either direct uptake of GSH or stimulation of its intracellular synthesis. The protective effects of glutathione against hypoxic and cyanide-induced hepatotoxicity substantiate the role of oxidative stress in both types of injury.

Animals↗
PubMed1990

Experimental studies on the acute cardiovascular toxicity of formalin and its antidotal treatment.

Rats anesthetized with pentobarbital and ventilated artificially were infused with 0.01 ml formalin (= 0.12 mmol formaldehyde)/kg.min. They exhibited a sharp decline of arterial blood pressure, heart rate and peripheral resistance and a slower one of cardiac output and died after 59.9 +/- 6.0 min of infusion. Sinus bradycardia and, in some cases, AV-arrhythmia occurred in the ECG. The additional infusion with cysteine attenuated the cardiovascular failure and more than doubled the survival time of formalin-infused rats. Infusion of N-acetylcysteine or correction of formalin-induced metabolic acidosis with sodium bicarbonate, on the other hand, did not exert antidotal activity. On isolated rat atria in vitro, formalin decreased the rate and the contractility and cysteine antagonized these effects of formalin. In conclusion, the severe and often lethal incidents observed following the therapeutic administration of formalin are due to the cardiovascular-depressive activity of formaldehyde and may be antagonized by cysteine.

Acetylcysteine↗
PubMed1990

[Methods of toxicologic evaluation--possibilities and limits].

Toxicological knowledge is founded on observation in humans consisting of casuistic presentations and epidemiologic research and on animal experiments. The possibilities and limitations of these sources of knowledge are presented with special reference to the problems of the dose and of toxic interactions. The limitations of toxicological knowledge primarily result from the impossibility to prove "no action". Therefore, it is not possible to prove the absolute safety of a substance but only the acceptability by assessing its advantages and risks.

Animals↗
PubMed1990

Studies of antidote therapy for nisoldipine intoxication in experimental animals.

In anesthetized rats under artificial respiration, intravenous infusion of nisoldipine (0.1 mg/kg x min) caused significant decreases in blood pressure, heart rate, cardiac output and peripheral resistance. The animals died 54.7 +/- 11.1 min after initiation of the infusion. The electrocardiogram showed sinus bradycardia, increasing AV blockade and displacement of the pacemaker into the AV node or the bundle of His. Survival time under nisoldipine infusion increased more than two-fold with simultaneous infusion of calcium gluconate, isoprenaline (isoproterenol) or dopamine. Norepinephrine (noradrenaline) had no significant effect on survival time; the latter decreased to 19.4 +/- 1.6 min by plasma volume expansion with polygeline. All antidotes prolonging survival time also normalized the cardiac output diminished after nisoldipine. Electrocardiographic changes were antagonized only by isoprenaline. Suitable antidotes for intoxication or over-dosage of nisoldipine are calcium salts as well as beta-sympathomimetic drugs; sheer volume substitution and peripheral vascular constriction should not be resorted to.

Animals↗
PubMed1990

[Effects of amalgam fillings on the mercury concentrations in amniotic fluid and breast milk].

Human amniotic fluid was gained from 95 pregnant women by amniocentesis (group 1) and from 20 women during delivery (group 2). The concentrations of inorganic mercury in amniotic fluid as assessed directly by cold-vapor atomic absorption spectrophotometry (CV-AAS) averaged 0.29 +/- 0.1 microgram/l in group 1 and 0.86 +/- 0.25 microgram/l in group 2. Surface areas of dental amalgam fillings were also estimated in these women and ranged between 0 and 930 mm2. There was no correlation between the surface area of maternal amalgam fillings and the concentrations of inorganic mercury in amniotic fluid (r = -0.122 and -0.069, respectively). Furthermore, no positive correlation existed between amalgam fillings and the concentration of total mercury in maternal blood (4.48 +/- 2.33 micrograms/l) and in neonatal blood (3.28 +/- 1.57 micrograms/l) as measured by CV-AAS in group 2 (r = -0.4 and -0.12, respectively). Concentrations of total mercury were also measured by CV-AAS in the breast milk of 86 women, five to ten days after delivery. These concentrations averaged 1.9 +/- 1.6 micrograms/l and were also not significantly correlated to the maternal amalgam surface areas (r = 0.188). In conclusion, maternal amalgam fillings are of no importance for the mercury load of the fetus and the neonate.

Adolescent↗
PubMed1989

Enhancement of acute ethanol hepatotoxicity under conditions of low oxygen supply and ischemia/reperfusion. The role of oxygen radicals.

Using isolated hemoglobin-free perfused rat livers we studied the effect of low oxygen supply on ethanol hepatotoxicity in two models. In the first model resembling low blood supply, perfusion rate was lowered from 60 to 10 ml/min after a 30 min-equilibration phase and kept low for 60 min. As a consequence, oxygen consumption fell from 1.76 +/- 0.15 mumol/min/g to 0.51 +/- 0.02 mumol/min/g. In the second model, total ischemia was accomplished by interruption of the perfusion for 30 min and was followed by reperfusion at a perfusion rate of 60 ml/min for a further 30 min. In this model, oxygen consumption returned immediately to normal values upon reperfusion. In both models, low oxygen supply had no toxic effects of its own on livers from fed rats. While ethanol (3 g/l) given under normoxic conditions led to a moderate hepatotoxicity, its application in both models of partial as well as total ischemia and reperfusion resulted in a marked liver damage as evidenced by a strong release of sorbitol dehydrogenase, glutamate-pyruvate-transaminase, lactate dehydrogenase and glutathione, as well as by an increase in hepatic calcium content. Inhibition of ethanol metabolism by 4-methylpyrazol prevented liver damage in both models indicating that metabolism of ethanol is a prerequisite for its toxicity to occur. Also, hepatotoxicity was inhibited partially by catalase and superoxide dismutase and nearly totally by deferrioxamine and allopurinol. Thus, reactive oxygen species which are produced during ethanol metabolism as well as under conditions of low oxygen supply are mediators of hepatic damage in both models employed.

Animals↗