ABSTRACT
Lindane administration to rats (60 mg/kg b.w.) led to an enhancement in the oxidative stress status of the liver at 4 h after treatment, characterized by increases in hepatic thiobarbituric acid reactants (TBARS) formation and chemiluminescence, reduced glutathione (GSH) depletion, and diminution in the biliary content and release of GSH. These changes were observed in the absence of changes in either microsomal functions (cytochrome P450 content, NADPH-dependent superoxide radical production, and NADPH-cytochrome P450 reductase or NADPH oxidase activities) or in oxidative stress-related enzymatic activities (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and glutathione-S-transferases), over control values. Phenobarbital (PB) administration (0.1% in drinking water; 15 days) elicited an enhancement in liver microsomal functions, lipid peroxidation, and GSH content, without changes in oxidative stress-related enzymatic activities, except for the elevation in those of glutathione reductase and glutathione-S-transferase, compared to control rats. Lindane given to PB-pretreated rats did not alter liver microsomal functions, lipid peroxidation, glutathione status, or oxidative stress-related enzymatic activities, as compared to PB-pretreated animals. In addition, lindane induced periportal necrosis with hemorrhagic foci in untreated rats, but not in PB-pretreated animals. It is concluded that the early oxidative stress response of the liver to lindane and hepatic injury are suppressed by PB pretreatment via induction of microsomal enzymes in all zones of the hepatic acinus. reserved.
Subject(s)
Hexachlorocyclohexane/poisoning , Liver Diseases/prevention & control , Oxidative Stress/drug effects , Phenobarbital/pharmacology , Acute Disease , Animals , Biotransformation , Chemical and Drug Induced Liver Injury , Excitatory Amino Acid Antagonists/pharmacology , Hexachlorocyclohexane/antagonists & inhibitors , Hexachlorocyclohexane/blood , Lipid Peroxidation/drug effects , Liver/drug effects , Male , Rats , Rats, WistarABSTRACT
The association between an in vivo oxidative stress condition of the liver and hepatic porphyria during HCB intoxication is postulated. After 30 days of treatment, HCB (25 mg/kg b.w.) promotes an induction of microsomal cytochrome P450 system, increase in microsomal superoxide anion generation accompanied by increased levels of liver lipid peroxidation, as measured by the production of thiobarbituric acid reactants and by spontaneous visible chemiluminescence. Concomitantly, liver antioxidant defenses are slightly modified, with decreased activity of glutathione peroxidase, superoxide dismutase and glucose-6-phosphate dehydrogenase contributing to an oxidative stress condition of the liver. These liver biochemical alterations are closely related to increased levels of urinary coproporphyrin, plasma AST and ALT activities and to the onset of liver morphological lesions.
Subject(s)
Fungicides, Industrial/toxicity , Hexachlorobenzene/toxicity , Liver/drug effects , Animals , Coproporphyrins/urine , Cytochrome P-450 Enzyme System/metabolism , Erythrocytes/drug effects , Glutathione Peroxidase/metabolism , Liver/metabolism , Male , Oxidative Stress , Porphyrias/chemically induced , Porphyrias/metabolism , Rats , Rats, WistarABSTRACT
Changes in rat liver oxidative stress-related parameters, morphological alterations, as well as circulating and tissue levels of lindane were studied 1-7 days after the administration of a single dose of 60 mg of lindane/kg. One day after lindane treatment, a significant enhancement in the oxidative stress status of the liver was observed, characterized by an increase in thiobarbituric acid reactants production and in the microsomal generation of superoxide radical (O.-2) coupled to cytochrome P450 induction, and a decrement in the activity of superoxide dismutase (SOD) and catalase. Consequently, the O.-2 production/SOD activity ratio was enhanced two-fold. In this condition, light microscopy studies revealed the incidence of liver lesions in periportal areas, together with significant changes at the mitochondrial level observed by electron microscopy, which coincide with the maximal levels of lindane in the liver, adipose tissue, plasma and whole blood. Changes in oxidative stress-related parameters observed after 1 day of lindane treatment regressed to normal from the third day and thereafter, together with the decrement in circulating and tissue levels of the insecticide. It is concluded that morphological and oxidative stress-related changes induced in the liver by acute lindane intoxication are readily reversible, depend on the hepatic content of the insecticide, and seem to be conditioned by the changes in O.-2 generation.
Subject(s)
Hexachlorocyclohexane/toxicity , Liver/drug effects , Oxidative Stress/drug effects , Adipose Tissue/chemistry , Animals , Catalase/drug effects , Catalase/metabolism , Hexachlorocyclohexane/blood , Hexachlorocyclohexane/pharmacokinetics , In Vitro Techniques , Liver/metabolism , Liver/pathology , Male , Microscopy, Electron , Mitochondria/ultrastructure , Organelles/ultrastructure , Rats , Rats, Wistar , Superoxide Dismutase/drug effects , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolism , Tissue DistributionABSTRACT
On the basis of the well-known effect of ethanol poisoning on the prooxidant/antioxidant balance of human and rodent liver we tested the response of the mitochondrial manganese-containing superoxide dismutase (MnSOD) in the liver of rats following an acute ethanol load or chronically intoxicated with an alcohol-supplemented solid diet for three weeks. In both conditions the enzyme activity and messenger RNA were monitored. In the acutely treated animals MnSOD was induced (post-)translationally already at 3 hours after ethanol injection, reached the maximum level (about 50% increment) at 9 hours and decreased thereafter. Chronic ethanol feeding caused an up-regulation of the enzyme at the mRNA level, with a good correlation between the transcript and the enzyme activity during the first two weeks of treatment. After 20 days the mRNA level dropped to normal, whereas the activity still remained high. Chronic alcohol intake also led to a significant decrease in the content of vitamin E in the liver mitochondrial and microsomal fractions, suggesting the occurrence of an enhanced lipid peroxidation, consequent to the ethanol-induced oxidative stress. The response of MnSOD appears to be a protective mechanism that the genetic machinery builds up to partially overcome such a condition.
Subject(s)
Alcoholism/enzymology , Mitochondria, Liver/enzymology , Superoxide Dismutase/metabolism , Acute Disease , Animals , Chronic Disease , Gene Expression , Intracellular Membranes/metabolism , Male , Metals/metabolism , RNA, Messenger/genetics , Rats , Rats, Wistar , Vitamin E/metabolismABSTRACT
1. Livers from rats treated acutely with ethanol showed increased chemiluminescence, malondialdehyde production, and diene formation. Previous administration of (+)-cyanidanol-3 completely abolished acute ethanol-induced chemiluminescence. 2. Rats fed alcohol liquid diets for 3 weeks showed significant increases in microsomal and mitochondrial malondialdehyde formation, and in microsomal H2O2 and O2-. generation. 3. Rats fed a solid basal diet plus ethanol solution for 12 weeks also showed increased microsomal production of O2-. and increased content of microsomal cytochrome P-450. Hydroperoxide-induced chemiluminescence was higher in homogenates, mitochondria and microsomes from ethanol-treated rats than from controls. Vitamins E and A were more effective inhibitors of hydroperoxide-stimulated chemiluminescence in liver homogenates from ethanol-treated rats than from control animals. 4. Results are consistent with peroxidative stress leading to increased lipid peroxidation in liver of rats fed ethanol both acutely and after long-term dosing.
Subject(s)
Ethanol/toxicity , Liver/metabolism , Stress, Physiological/metabolism , Animals , Antioxidants/metabolism , Catechin/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Cytosol/drug effects , Cytosol/metabolism , Hydrogen Peroxide/pharmacology , Luminescent Measurements , Male , Malondialdehyde/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mitochondria, Liver/drug effects , Mitochondria, Liver/metabolism , Oxidation-Reduction , Rats , Rats, Inbred Strains , Stress, Physiological/chemically induced , Subcellular Fractions/drug effects , Subcellular Fractions/enzymology , Superoxide Dismutase/metabolismABSTRACT
1. Lindane (60 mg/kg) administered orally to rats increased liver cytochrome P-450 content and superoxide radical (O2-.) generation 24 h after treatment, while formation of thiobarbituric acid reactants and NADPH/ADP-supported microsomal chemiluminescence were significantly increased 4 h after treatment. 2. Hepatic superoxide dismutase (SOD) and catalase decreased 6 h after lindane treatment and SOD/O2-. ratio progressively decreased during 4 to 24 h after lindane treatment. 3. Morphological evidence of hepatic cell injury after lindane treatment was seen at all times studied, and appeared to increase with time. 4. Lindane administration results in time-dependent oxidative stress in liver which involves an early component (4-6 h) related to the reductive metabolism of lindane, and a late component (24 h) associated with the induction of cytochrome P-450; the biochemical changes correlated with the observed morphological lesions.
Subject(s)
Hexachlorocyclohexane/toxicity , Lipid Peroxides/metabolism , Microsomes, Liver/drug effects , Animals , Catalase/metabolism , Cytochrome P-450 Enzyme System/metabolism , Kinetics , Male , Microsomes, Liver/metabolism , Microsomes, Liver/pathology , Oxidation-Reduction , Rats , Rats, Inbred Strains , Stress, Physiological/metabolism , Stress, Physiological/pathology , Superoxide Dismutase/metabolism , Superoxides/metabolism , Thiobarbiturates/metabolismABSTRACT
Mitochondrial mass was determined in the heart and liver of rats submitted to 4,400 m (simulated altitude) for 9 mo and their controls at sea level. This was done 1) by evaluation of isolated mitochondrial protein per gram of tissue, 2) by evaluation of the ratio between cytochrome oxidase activity in tissue homogenate and in isolated mitochondria, and 3) by evaluation of mitochondrial numerical and volume density in fixed tissues analyzed by electron microscopy. An increase in mitochondrial mass and a more homogeneous distribution of mitochondria were found in liver. In cardiac tissue an increase in numerical density of mitochondria accompanied by a slight decrease in their mean volume was observed. Maximal physiological rate of mitochondrial respiration (state 3, active respiration), resting respiration, ADP/O, and acceptor control ratio were determined in the isolated mitochondria. No differences were found in the intrinsic properties of mitochondria. The results suggest that chronic mild hypoxia promotes tissue adaptation by increasing the mitochondrial mass or number in liver and heart, respectively, and improves intracellular O2 diffusion by adopting a more homogeneous intracellular distribution of mitochondria in the liver.
Subject(s)
Hypoxia/pathology , Mitochondria, Heart/ultrastructure , Mitochondria, Liver/ultrastructure , Animals , Electron Transport Complex IV/metabolism , Female , Hydrogen-Ion Concentration , Male , Oxygen Consumption , Rats , Rats, Inbred StrainsABSTRACT
The role of vitamin E and selenium as protective agents against oxidative stress was evaluated by measuring liver chemiluminescence in situ. Weanling rats fed a vitamin E- and selenium-deficient diet showed liver chemiluminescence that was increased 60 and 100% over control values at 16 and 18 days respectively after weaning. At day 21, the double deficiency led to hepatic necrosis, as observed by optical and electron microscopy, and increased serum levels of lactate dehydrogenase and alanine aminotransferase. Single deficiencies, in either vitamin E or selenium, did not produce liver necrosis but increased liver chemiluminescence. Vitamin E deficiency led to a 23 and 50% increase in liver emission at days 18 and 20 respectively; selenium deficiency produced a 64% increase at day 16. The activity of liver selenium-glutathione peroxidase diminished to 13% of the control value in the rats fed doubly deficient and selenium-deficient diets. Activities of superoxide dismutase, catalase and non-selenium-glutathione peroxidase were not modified by the different diets. These results suggest that oxy-radical generation may play a major role in hepatic necrosis in vitamin E- and selenium-deficiency.
Subject(s)
Liver/metabolism , Selenium/deficiency , Vitamin E Deficiency/metabolism , Animals , Glutathione Peroxidase/metabolism , Liver/enzymology , Liver/pathology , Luminescent Measurements , Male , Necrosis , Oxidation-Reduction , Rats , Rats, Inbred Strains , Vitamin E Deficiency/pathologySubject(s)
Jaundice/complications , Tuberculosis, Pulmonary/complications , Adolescent , Adult , Aged , Antitubercular Agents/administration & dosage , Antitubercular Agents/adverse effects , Female , Humans , Jaundice/chemically induced , Liver Diseases/complications , Male , Middle Aged , Prognosis , Tuberculosis, Pulmonary/drug therapySubject(s)
Liver/drug effects , Pyrazinamide/adverse effects , Tuberculosis, Pulmonary/drug therapy , Adolescent , Adult , Aged , Alcoholism/complications , Antitubercular Agents/adverse effects , Antitubercular Agents/therapeutic use , Endoplasmic Reticulum/ultrastructure , Humans , Liver/ultrastructure , Male , Middle Aged , Mitochondria, Liver/ultrastructure , Pyrazinamide/therapeutic use , Tuberculosis, Pulmonary/complicationsABSTRACT
Se estudió la influencia de la vinblastina, droga que causa inhbición de la polimerización de la tubulina a microtúbulos, sobre la secreción biliar y la ultraestructura hepática en ratas. La vinblastina fue administrada endovenosamente a la dosis de 2mg por 100g p.c., 2 horas antes de efectuar el estudio. Se observó lo seguiente: 1) el flujo biliar basal y la secreción basal de ácidos biliares no fueron modificados: 2) el flujo biliar y la secreción de ácidos biliares disminuyeron después de una sobrecarga de ácidos biliares, y 3) el examen de microscopía electrónica de los hepatocitos, en los animales tratados con vinblastina, reveló la desaparición casi completa de los microtúbulos, un aumento en el número y tamaño de las vesículas de lipoproteína de muy baja densidad, y la configuración anormal de mitocondrias caracterizada por un aumento de la densidad matrical y figuras de partición. Estos resultados apoyan la hipótesis sobre la partición de los microtúbulos en los mecanismos de secreción biliar, además de demostrar una acción de la vinblastina sobre la estructura mitocondrial (AU)
Subject(s)
Rats , Animals , Male , Bile/metabolism , Liver/ultrastructure , Vinblastine/pharmacology , Bile Acids and Salts/metabolism , Alanine Transaminase/blood , Microscopy, ElectronABSTRACT
Un grupo de pacientes tuberculosos, varones, adultos, sin enfermedades asociadas, alcoholikas y no alcoholistas, recibieron un esquema terapéutico con isoniacida, rifampicina, estreptomicina y pirazinamida, a las dosis corrientes. Se les efectuó un estudio funcional e histológico del hígado antes del tratamiento y se lo repitió a los 2 meses de recibir las drogas. Un grupo control, estudiado de la misma manera, recibió un esquema terapéutico con isoniacida, rifampicina, estreptomicina y etambutal. Otro grupo de pacientes tuberculosos recibió pirazinamida sola durante 2 semanas y el hígado también fue estudiado antes y después de la quimioterapia. En todos los casos, las muestras hepáticas obtenidas a los 2 meses de recibir drogas asociadas y a las 2 semanas de recibir pirazinamida sola fueron observadas con microscopía electrónica. En los pacientes que recibieron pirazinamida sola el estudio ultraestructural del hígado mostró 3 casos normales y megamitocondrias y/o hiperplasia del retículo endoplásmico liso en los 4 casos restantes. Los pacientes que recibieron un esquema asociado con pirazinamida presentaban a los 2 meses analogas alteraciones hepáticas: megamitocondrias, hiperplasia del retículo endoplásmico liso, solas o asociadas. El grupo control, tratado con un esquema sin pirazinamida, mostró modificaciones ultraestructurales análogas a las del grupo anterior, salvo 1 caso con dilatación del retículo endoplásmico rugoso. En ninguno de los 3 grupos hubo diferencias entre los pacientes alcoholistas y no alcoholistas, y las alteraciones ultraestructurales halladas no tuvieron repercusión clínica ni funcional. Teniendo en cuenta que las alteraciones ultraestructurales del hepatocito observadas en estos pacientes son frecuentes en varias enfermedades hepáticas y que las pueden producir varias drogas incluyendo las drogas antituberculosas, no se las puede considerar privativas de la pirazinamida. Podemos concluir que el empleo de la pirazinamida en el tratamiento de la tuberculosis en pacientes alcoholistas y no alcoholistas, sin enfermedad hepática asociada, y con las característica terapÛuticas con que se la maneja actualmente, no aumenta el riesgo hepático que implica el uso de las otras drogas (AU)
Subject(s)
Adolescent , Adult , Middle Aged , Aged , Humans , Male , Liver/drug effects , Pyrazinamide/pharmacology , Tuberculosis, Pulmonary/drug therapy , Drug Administration Schedule , Liver/ultrastructure , Pyrazinamide/therapeutic useABSTRACT
Se llevó a cabo una experiencia educacional de complementación de las unidades temáticas de Patología con clases teóricas sobre aspectos clínicos dictados por docentes de Medicina Interna. El diseño controlado del estudio permitió verificar en las evaluaciones con pruebas estructuradas sobre Patología una diferencia significativa o favor de los alumnos que participaron en las clases sobre clínica. La experiencia piloto contó con la aceptación y colaboración de docentes y alumnos (AU)
Subject(s)
Humans , Pathology/education , Faculty , Internal MedicineABSTRACT
Se estudió la influencia de la vinblastina, droga que causa inhbición de la polimerización de la tubulina a microtúbulos, sobre la secreción biliar y la ultraestructura hepática en ratas. La vinblastina fue administrada endovenosamente a la dosis de 2mg por 100g p.c., 2 horas antes de efectuar el estudio. Se observó lo seguiente: 1) el flujo biliar basal y la secreción basal de ácidos biliares no fueron modificados: 2) el flujo biliar y la secreción de ácidos biliares disminuyeron después de una sobrecarga de ácidos biliares, y 3) el examen de microscopía electrónica de los hepatocitos, en los animales tratados con vinblastina, reveló la desaparición casi completa de los microtúbulos, un aumento en el número y tamaño de las vesículas de lipoproteína de muy baja densidad, y la configuración anormal de mitocondrias caracterizada por un aumento de la densidad matrical y figuras de partición. Estos resultados apoyan la hipótesis sobre la partición de los microtúbulos en los mecanismos de secreción biliar, además de demostrar una acción de la vinblastina sobre la estructura mitocondrial
Subject(s)
Rats , Animals , Male , Bile Acids and Salts , Bile/metabolism , Liver/ultrastructure , Vinblastine/pharmacology , Alanine Transaminase/blood , Microscopy, ElectronABSTRACT
Un grupo de pacientes tuberculosos, varones, adultos, sin enfermedades asociadas, alcoholikas y no alcoholistas, recibieron un esquema terapéutico con isoniacida, rifampicina, estreptomicina y pirazinamida, a las dosis corrientes. Se les efectuó un estudio funcional e histológico del hígado antes del tratamiento y se lo repitió a los 2 meses de recibir las drogas. Un grupo control, estudiado de la misma manera, recibió un esquema terapéutico con isoniacida, rifampicina, estreptomicina y etambutal. Otro grupo de pacientes tuberculosos recibió pirazinamida sola durante 2 semanas y el hígado también fue estudiado antes y después de la quimioterapia. En todos los casos, las muestras hepáticas obtenidas a los 2 meses de recibir drogas asociadas y a las 2 semanas de recibir pirazinamida sola fueron observadas con microscopía electrónica. En los pacientes que recibieron pirazinamida sola el estudio ultraestructural del hígado mostró 3 casos normales y megamitocondrias y/o hiperplasia del retículo endoplásmico liso en los 4 casos restantes. Los pacientes que recibieron un esquema asociado con pirazinamida presentaban a los 2 meses analogas alteraciones hepáticas: megamitocondrias, hiperplasia del retículo endoplásmico liso, solas o asociadas. El grupo control, tratado con un esquema sin pirazinamida, mostró modificaciones ultraestructurales análogas a las del grupo anterior, salvo 1 caso con dilatación del retículo endoplásmico rugoso. En ninguno de los 3 grupos hubo diferencias entre los pacientes alcoholistas y no alcoholistas, y las alteraciones ultraestructurales halladas no tuvieron repercusión clínica ni funcional. Teniendo en cuenta que las alteraciones ultraestructurales del hepatocito observadas en estos pacientes son frecuentes en varias enfermedades hepáticas y que las pueden producir varias drogas incluyendo las drogas antituberculosas, no se las puede considerar privativas de la pirazinamida. Podemos concluir que el empleo de la pirazinamida en el tratamiento de la tuberculosis en pacientes alcoholistas y no alcoholistas, sin enfermedad hepática asociada, y con las característica terapêuticas con que se la maneja actualmente, no aumenta el riesgo hepático que implica el uso de las otras drogas
Subject(s)
Adolescent , Adult , Middle Aged , Humans , Male , Liver/drug effects , Pyrazinamide/pharmacology , Tuberculosis, Pulmonary/drug therapy , Drug Administration Schedule , Liver/ultrastructure , Pyrazinamide/therapeutic useABSTRACT
Se llevó a cabo una experiencia educacional de complementación de las unidades temáticas de Patología con clases teóricas sobre aspectos clínicos dictados por docentes de Medicina Interna. El diseño controlado del estudio permitió verificar en las evaluaciones con pruebas estructuradas sobre Patología una diferencia significativa o favor de los alumnos que participaron en las clases sobre clínica. La experiencia piloto contó con la aceptación y colaboración de docentes y alumnos
