ABSTRACT
The authors demonstrated the generation of a very reactive phenyl radical from amiodarone in a reducing molecular environment by pulse radiolysis study. The various antioxidants are probably not capable of preventing the generation of phenyl radical, as well as to protect against its damaging effects on the neighboring molecules. Electron microscopic studies from lung tissue of in vivo treated rats showed that the simultaneous Silibinin (a flavonoid type antioxidant) treatment with amiodarone decreased significantly the lysosomal phospholipoidosis induced by amiodarone compared with the amiodarone treated group, but it didn't prevent entirely the accumulation of lysosomal phospholipids. The in vitro lysosomal beta-glucuronidase enzyme release measured from the liver tissue of in vivo treated rats increased significantly on amiodarone treatment, the antioxidants used (Silibinin, and the dihydroquinoline type MTDQ-DA) didn't exert any favorable effect. The authors discuss in details the possible relationships between free radical reactions and lysosomal phospholipoidosis.
Subject(s)
Amiodarone/adverse effects , Antioxidants/pharmacology , Amiodarone/antagonists & inhibitors , Animals , Chemical and Drug Induced Liver Injury/prevention & control , Drug Evaluation, Preclinical/methods , Free Radicals , In Vitro Techniques , Liver/enzymology , Liver/ultrastructure , Lysosomes/drug effects , Pulse Radiolysis , Rats , Spectrum AnalysisABSTRACT
The antiatherosclerotic profile of nicotinic acid and of its new water-insoluble derivative was studied in an 8-day experiment in rats. Both drugs lowered plasma triglyceride levels significantly, while other lipoprotein parameters were unaffected. Circulating immune complex levels were decreased with lysosomal membrane permeability by both drugs. Glunicate proved to be a powerful antioxidant with regard to enzymatic lipid peroxidation when studied in the liver microsomal system. The relevance of these findings to the antiatherosclerotic effect of the drugs and the biological significance of antioxidant treatment is discussed. On the basis of these data glunicate seems to be a promising new therapeutic tool against atherosclerosis and merits further study.
Subject(s)
Diet, Atherogenic , Lipid Peroxides/metabolism , Lipids/blood , Niacinamide/analogs & derivatives , Acid Phosphatase/blood , Animals , Antigen-Antibody Complex/analysis , Cholesterol/blood , Glucuronidase/blood , Lipoproteins/blood , Male , Niacin/pharmacology , Niacinamide/pharmacology , Rats , Rats, Inbred Strains , Triglycerides/bloodABSTRACT
Lysosomal acid phosphatase, beta-glucuronidase, and cathepsin-D were studied in liver cell fractions of rats regularly exercised by swimming. On the 21st day of the training, enzyme activities in the extralysosomal fraction and in the lysosomal fraction were higher and lower, respectively, than in the untrained controls. On the 40th day an increased enzyme activity was found in both fractions. By the end of the training period (54th and 80th days), a slightly decreased activity was recorded in both fractions. Lysosomal membrane permeability for enzymes was higher during the first period of the training, in particular when estimated under hypotonic conditions. Regular swimming training or 12-day treatment by ACTH stabilized the membrane of the liver lysosomes. This stabilization was believed to be mediated by corticosteroids mobilized by exercise or by the administration of ACTH.
Subject(s)
Liver/enzymology , Lysosomes/enzymology , Physical Conditioning, Animal , Swimming , Acid Phosphatase/analysis , Animals , Cathepsin D , Cathepsins/analysis , Cell Membrane Permeability , Glucuronidase/analysis , Rats , Time FactorsABSTRACT
In accordance with the clonal selection theory the authors intended to prevent the development of autoimmune hepatitis in rabbits with the aid of radiolabelled liver specific membrane (LSP) antigen administered prior to the antigen immunization. The autoimmune hepatitis was produced in rabbits by allogen LSP antigen. The inflammatory reaction was characterized by the serum glutamic oxaloacetic transaminase activity in the sera, by the parameters of immune reaction as well as by lysosomal membrane alterations in the liver and by morphological findings. The process was inhibited by pre-treatment with hot labelled LSP antigen. Neither the radioactively labelled growth hormone pre-treatment, nor the application of hot labelled antigen at the last week of the experiment were able to prevent the humoral and lysosomal, as well as the morphological data characteristic for autoimmune hepatitis. The results obtained may be understood considering the mechanism of clonal selection.
Subject(s)
Antigens, Surface/immunology , Autoimmune Diseases/prevention & control , Hepatitis/prevention & control , Immunization , Liver/immunology , Membrane Proteins , Proteins/immunology , Animals , Aspartate Aminotransferases/blood , Body Weight , Hepatitis/pathology , Iodine Radioisotopes/therapeutic use , Lipoproteins/immunology , Liver/pathology , Lysosomes/enzymology , Male , Organ Size , Rabbits , Spleen/pathologyABSTRACT
The authors examined the effect in vivo and in vitro of Catergen (cyanidanol-3) on demonstrable lysosomal enzyme activity in the serum and granulocytes in liver diseases. Acid phosphatase, cathepsin-D and beta-glucuronidase were investigated. In the in vitro studies the direct effect of Catergen was observed by enzyme release. In chronic active hepatitis without treatment the lysosomal activity of the serum increases, the lysosomal activity of the granulocytes decreases and in vitro release increases. Under the effects of Catergen treatment the lysosomal activity of the serum decreases in comparison with initial values, approaching the lysosomal enzyme activity observed in healthy persons. Under in vitro conditions, lysosomal enzyme release from the granulocytes decreases in treated individuals and thus a higher lysosomal enzyme activity in the granulocytes is observed. Granulocytes separated from the blood of healthy persons were incubated with Catergen in isotonic and hypotonic media. In an isotonic medium the release did not change significantly. Under the effect of hypotension the release of lysosomal enzyme increased considerably. In vitro incubation with small doses of Catergen significantly inhibited the degree of release. On the basis of these data it may be supposed that Catergen has a stabilizing effect on the lysosomal membrane and is thus beneficial in the treatment of liver injuries (alcoholic, toxic, inflammatory) with lysosomal membrane alterations.
Subject(s)
Benzopyrans/pharmacology , Catechin/pharmacology , Granulocytes/enzymology , Hepatitis/enzymology , Lysosomes/enzymology , Acid Phosphatase/blood , Adolescent , Adult , Aged , Cathepsin D , Cathepsins/blood , Cell Membrane Permeability/drug effects , Female , Free Radicals , Glucuronidase/blood , Granulocytes/drug effects , Hepatitis/drug therapy , Hepatitis, Chronic/enzymology , Humans , Lysosomes/drug effects , Male , Middle AgedABSTRACT
In the therapy of chronic liver diseases several drugs are currently used. This review summarizes the results of the authors in the therapy of chronic liver diseases with cyanidanol-3, as well as the beneficial effects of the new dihydroquinoline-type antioxidants in acute carbon tetrachloride induced and galactosamine induced liver lesions. In addition, the immunostimulant effects of Aicaphosphate is demonstrated in chronic active hepatitis.
Subject(s)
Liver Diseases/drug therapy , Liver/drug effects , Animals , Catechin/therapeutic use , Chemical and Drug Induced Liver Injury/drug therapy , Chronic Disease , Enzymes/blood , Granulocytes/drug effects , Granulocytes/enzymology , Hepatitis, Chronic/drug therapy , Humans , Liver Diseases/enzymology , Lysosomes/drug effects , Lysosomes/enzymology , Malondialdehyde/metabolism , Mice , Quinolines/therapeutic useABSTRACT
The influence of a new dihydroquinoline type antioxidant on doxorubicin-induced hepatic toxicity was studied in mice (CFLP, LATI). Four groups of mice were studied: control, doxorubicin-treated, 5,6-methylen-bis (2,2,4/-trimethyl-1,2-dihydroquinoline/-disulphate (MDS)-treated, as well as doxorubicin and MDS-treated groups. Doxorubicin (15 mg/kg) was administered intraperitoneally, the MDS solution was given by a gastric tube. Liver function was assessed by the serum glutaminic-oxaloacetic-transaminase (SGOT) reaction. The lipid peroxidation in liver tissue was determined by the rate of malondialdehyd (MDA) production, the permeability of the liver lysosomal membrane was established by measuring beta-glucuronidase activity and its release from the cells. The MDS treatment proved to be effective in significantly reducing SGOT elevation, MDA production and lysosomal membrane damage in hepatic tissue. Clinical trials seem to be justified in using antioxidative substances to control doxorubicin toxicity.
Subject(s)
Antioxidants/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Doxorubicin/toxicity , Liver/drug effects , Quinolines/pharmacology , Animals , Aspartate Aminotransferases/metabolism , Glucuronidase/metabolism , Male , Malondialdehyde/metabolism , Mice , Mice, Inbred StrainsSubject(s)
Fatty Liver, Alcoholic/blood , Liver Cirrhosis, Alcoholic/blood , Aged , Anemia/etiology , Anemia, Hypochromic/etiology , Blood Cell Count , Fatty Liver, Alcoholic/complications , Female , Ferritins/blood , Humans , Liver Cirrhosis, Alcoholic/complications , Male , Middle Aged , Vitamins/bloodABSTRACT
The pharmacological action and possible therapeutic uses of some recently developed synthetic, non-toxic dihydroquinoline-type antioxidants were studied. The effect of the lipid-soluble 6,6-methylene-bis (2,2,4-trimethyl-1,2-dihydroquinoline) (n = 1, 2 or 3) (MTDQ) on carbon-tetrachloride-induced acute liver injuries was investigated, and that of the water-soluble 6,6-methylene-bis (2,2-dimethyl-4-methansulphonic acid sodium-1,2-dihydroquinoline) (MDS) on galactosamine-induced acute liver injuries in CFLP mice (Lati, Hungary). MTDQ was found suitable for the prevention of acute CCl4-induced liver injuries and MDS for that of acute galactosamine-induced liver injuries. Disappearance or significant diminution of the morphological signs and lesions of lipid degeneration and centro-lobular liver necrosis, decrease of serum GOT activities, and also inflammatory changes induced by galactosamine were observed.
Subject(s)
Antioxidants , Carbon Tetrachloride Poisoning/complications , Chemical and Drug Induced Liver Injury , Galactosamine/poisoning , Quinolines/pharmacology , Animals , Aspartate Aminotransferases/blood , Fatty Liver/prevention & control , Inflammation/prevention & control , Liver/analysis , Malondialdehyde/analysis , Mice , Quinolines/therapeutic useABSTRACT
The authors examined the damage of lysosomal membrane caused by acute CCl4 intoxication by in vitro methods. They measured the acid phosphatase as well as beta-glucuronidase enzyme levels and determined the rate of release of these two enzymes. The in vivo changes in enzyme activity were extrapolated from the in vitro results. The CCl4 causes a significant increase in the permeability and rigidity of the lysosomal membrane. By oral and/or intraperitoneal administration of MTDQ the state of permeability can be improved or even corrected. On the basis of their results, the authors conclude that the lysosomal damage caused by CCl4 is mediated by peroxidation of lipids and the lysosomal membrane can be stabilised by MTDQ.
Subject(s)
Antioxidants/pharmacology , Carbon Tetrachloride/toxicity , Lysosomes/drug effects , Quinolines/pharmacology , Animals , Cell Membrane Permeability/drug effects , Female , In Vitro Techniques , Lysosomes/enzymology , Male , MiceABSTRACT
The authors have measured the activity of acid phosphatase, beta-glucuronaidase and cathepsin-D in tthe sera of patients with different liver diseases, and the actvity of beta-glucuronidase in granulocytes and the rate of its release. Using the method for the releaseof beta-glucuronidase from the granulocytes they drew conclusions to thedegree of the membrane-damage occurring in the liver diseases. They provided that in the sera of patients with different liver diseases the increase in the activity of the acid phosphatase and the beta-glucuronidase is different. According to their in vitro studies the decrease in the beta-glucuronidase activity measured in the granulocytes, and the release of enzyme is in connection with the type of liver disease and with the different degree of lysosomal membrane alteration.