Modifications of liver content of cyclic nucleotides in the rat poisoned with white phosphorus]

In rat liver following white phorphorus poisoning a biphasic increase in cyclic AMP concentration was observed. After a lag period of 1 hour the cyclic AMP content rose to a first peak at 4 hours and to a second peak at 12 hours of intoxication. The cyclic AMP level fell to normal after 24 hours, by which time the cyclic nucleotide concentration was approaching control values. On the contrary, cyclic GMP content was found to the normal level during the different stages of intoxication. Only at 36 hours the cyclic GMP amount appeared significantly increased above the control values. Serum activity of alanine- and aspartate-amino transferases was found changed from 8 hours to 24 hours after poisoning. The serum level of the two enzymes was overlapping the control values after 36 hours. These results are discussed in relation to hepatocyte necrosis following white phosphorus intoxication.     

Metal-binding capacity of metallothioneins of the liver of rats poisoned with heavy metals

The functioning of metallothioneins in the liver of rats, poisoned with copper sulfate and cadmium sulfate has been investigated. By sequential chromatography on sephadex G-50 and DEAE-cellulose the authors obtained metallothioneins (MT-1, MT-1A, MT-2, MT-2a), which differ in molecular weight and composition of associated metals. Heavy metal poisoning leads to activation of synthesis and metal-binding function of metallothioneins, as well as to changes in the composition of their isoforms.     

Studies on the electrogenic action of acetylcholine with Torpedo marmorata electric organ: I. Pharmacological properties of the electroplaque

The membrane potential (average = ?52 mV) of a freely exposed electroplaque from a dissected prism of Torpedo marmorata electric organ is recorded with an intracellular glass microelectrode. The resting potential decreases with external potassium concentration. Acetylcholine (in the presence of O,O′-diethyl S-(β-diethylamino)ethyl phosphorothiolate), decamethonium, phenyltrimethyl-ammonium and carbamylcholine added to the bath cause a decrease of membrane potential, i.e. behave as agonists. Their effect is blocked in a competitive manner by d-tubocurarine, gallamine and hexamethonium, and in a non-competitive way by prilocaine; 1 μg Erabutoxin/ml completely abolishes the response to carbamylcholine. The apparent dissociation constants for seven cholinergic ligands are determined from the dose-response curves, and found to be closely related to those previously determined with Electrophorus electricus electroplaque with, however, a few differences. During these experiments it was noticed that potassium ions affect, in a differential manner, the response of T. marmorata electroplaque to carbamylcholine and decamethonium.     

Behaviour of cyclic nucleotides and Ca2+ levels in liver tissue of rats poisoned by white phosphorus and trichlorobromomethane

The content of hepatic cyclic AMP was increased soon after intoxication by white phosphorus. Its level reached a maximum 4 h after poisoning, but in subsequent phases tended to return to normal. In contrast, the cyclic GMP concentration was altered only 24 and 36 h after treatment with the same hepatotoxin. Similar modifications of cAMP and cGMP content were also detected after poisoning by trichlorobromomethane (CBrCl3). As a consequence, an altered cGMP/cAMP ratio was found in both experimental conditions. Further, the modification of cAMP content after white phosphorus was detected prior to liver damage (steatosis and necrosis), while the highest concentration of the cyclic nucleotide in CBrCl3-poisoned rats was found when fatty liver was already evident. In addition, in phosphorus-poisoned rats, the hepatic content of Ca2+ was found to be unmodified during all phases of the intoxication, while after CBrCl3 a phasic increase of the Ca2+ level was observed at 4, 24 and 36 h.     

4-Hydroxyaminoquinoline 1-oxide metabolism and DNA adducts in the early stage of tumorigenesis in rats: comparison of target organ pancreas with non-target organ liver

In order to probe key early molecular events which might be responsible for the initiation of rat pancreatic tumorigenesis by 4-hydroxyaminoquinoline 1-oxide (4-HAQO), the uptake and metabolism of carcinogen and the formation and subsequent repair of DNA adducts were monitored under conditions of high and low tumorigenicity, respectively in partially pancreatectomized and non-operated animals, and in the liver, a non-target organ for this carcinogen. Although uptake of radioactively labelled 4-HAQO was higher in the liver than in the pancreas, generation of DNA adducts was 20 times greater in the latter organ. This discrepancy was probably due to a difference in the metabolic profile of 4-HAQO. The spectrum of the adducts was qualitatively similar in both organs. No qualitative or quantitative differences could be established under the high and low tumorigenicity conditions with regard to DNA adduct formation or persistence. The major difference was the presence of a relatively large extent of pancreatic DNA replication under the high tumorigenic condition. The results indicated that metabolic profile of 4-HAQO, quantity of DNA adducts and levels of DNA replication are key factors involved in initiation of tumorigenesis.     

Biochemical studies on the mechanism of action of liver poisons III. Depletion of liver glutathione in ethionine poisoning

Administration of ethionine to female rats was followed by rapid fall of the hepatic reduced glutathione content, concomitant with a progressive impairment of the cell-free protein-synthesizing capacity and a decline of the ATP level.In male rats and in adrenalectomized female rats, the onset of the first two alterations was considerably delayed. In contrast, the time course and the severity of the ethionine-induced ATP depletion were essentially the same in all instances.Treatment with CCl₄, despite the similarity of its hepatotoxic effects to those of ethionine, resulted in no appreciable decrease of the liver reduced glutathione level.Administration of methionine counteracted both the reduced glutathione decline and the other biochemical lesions induced by ethionine, whereas injection of adenine, though preventing the ATP depletion, failed to reverse the depression of reduced glutathione.The available evidence suggests that the decrease in the reduced glutathione level reflects a diminished capacity of the liver for oxidized glutathione reduction and its resultant inability to compensate the normal process of continuous reduced glutathione oxidation.The possible role of the altered reduced glutathione metabolism in the pathogenesis of ethionine hepatotoxicity is discussed.     

Protective effect of blackcurrant on liver cell membrane of rats intoxicated with ethanol

Chronic ethanol intoxication oxidative stress participates in the development of many diseases. Nutrition and the interaction of food nutrients with ethanol metabolism may modulate alcohol toxicity. One such compound is blackcurrant, which also has antioxidant abilities. We investigated the effect of blackcurrant as an antioxidant on the composition and electrical charge of liver cell membranes in ethanol-intoxicated rats. Qualitative and quantitative phospholipid composition and the presence of integral membrane proteins were determined by high-performance liquid chromatography. Electrophoresis was used to determine the surface charge density of the rat liver cell membranes. Ethanol intoxication is characterized by changes in cell metabolism that alter the structure and function of cell membrane components. Ethanol increased phospholipid levels and altered the level of integral proteins as determined by decreased phenylalanine, cysteine, and lysine. Ethanol significantly enhanced changes in the surface charge density of the liver cell membranes. Administration of blackcurrant to rats intoxicated with ethanol significantly protected lipids and proteins against oxidative modifications. It is possible that the beneficial effect of blackcurrant is connected with its abilities to scavenge free radicals and to chelate metal ions.