Animals ; Dietary Supplements ; Electron Transport ; Hypoxia ; Iron ; pharmacology ; Liver ; Mitochondria, Liver ; drug effects ; Rats

OBJECTIVETo explore the mitochondrial toxicities induced by zidovudine (AZT) and adefovir dipivoxil (ADV) antiviral drugs using a rat model system.

METHODSTwelve healthy Sprague-Dawley rats were randomly divided into three equal groups and treated by oral gavage with zidovudine (125 mg/kg/day), adefovir (40 mg/kg/day), or saline (equal volume) for 28 days. The rats' body weights were measured once a week, and blood was collected every two weeks for blood and biochemical tests. All animals were sacrificed at the end of treatment, and liver, kidney, skeletal muscle, and cardiac muscle were collected by necropsy. Mitochondria were isolated from the respective tissue samples, and the activities of respiratory chain complexes were measured. DNA was purified from each sample and the mitochondrial DNA (mtDNA) content was monitored by quantitative real time PCR. Mitochondrial morphology was analyzed under electron microscope.

RESULTSNo significant adverse effects, including body weight loss, abnormal blood or biochemistry, were observed in rats treated with AZT or ADV. The activities of mitochondrial cytochrome c oxidase in liver and cardiac muscle were slightly decreased in rats treated with AZT (liver: 9.44+/-3.09 vs. 17.8+/-12.38, P?=?0.21; cardiac muscle: 32.74+/-5.52 vs. 24.74+/-20.59, P?=?0.28; kidney: 4.42+/-1.53 vs. 14.45+/-13.75, P?=?0.18; skeletal muscle: 33.75+/-8.74 vs. 40.04+/-2.49, P?=?0.45). The mtDNA content was significantly decreased in cardiac muscle of AZT-treated rats (cardiac muscle: 0.15+/-0.13 vs. 0.32+/-0.42, P?=?0.85). The morphology of mitochondria in liver, kidney, skeletal muscle, and cardiac muscle was significantly altered in the AZT-treated rats and included disappearance of the outer membrane, severely damaged structure, and swollen or completely absent cristae. No obvious effects were noted in the ADV- or saline-treated rats.

CONCLUSIONSignificant adverse effects related to mitochondrial toxicity were observed in rats treated with AZT. The slightly decreased mtDNA content in ADV-treated rats may suggest that this antiviral drug can also cause mitochondrial toxic effects.

Adenine ; adverse effects ; analogs & derivatives ; Animals ; DNA, Mitochondrial ; drug effects ; Electron Transport Complex IV ; metabolism ; Female ; Kidney ; enzymology ; Liver ; enzymology ; Mitochondria ; drug effects ; metabolism ; Mitochondria, Heart ; drug effects ; Mitochondria, Liver ; drug effects ; Mitochondria, Muscle ; drug effects ; Muscle, Skeletal ; enzymology ; Myocardium ; enzymology ; Organophosphonates ; adverse effects ; Rats ; Rats, Sprague-Dawley ; Zidovudine ; adverse effects

OBJECTIVE: To find out the pathological change and the toxic mechanism of Chloranthus serratus Roem. et Schalt in mice. METHODS: Mice were intoxicated by oral administration with extracts of Chloranthus serratus Roem. et Schalt followed by pathological, serum biochemical, and coagulation mechanism examination. RESULTS: The LD50 in mice was 41.12 g/kg; All poisoned mice serum BUN and ALT increased markedly; Thrombocyte decreased and coagulation time increased; The organ index of liver, spleen and kidneys increased significantly; The cells of liver, kidney and heart were degeneration and necrosis, There were extensive hyperemia and hemorrhage in many organs. CONCLUSION The experiment suggests that the target organs were liver, kidney, heart and blood vessels; The toxic mechanism was the damage on the mitochondrional, endoplasmic reticulum and coagulation system.
Animals ; Biomarkers/blood* ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/drug effects* ; Female ; Forensic Pathology ; Kidney/pathology* ; Lethal Dose 50 ; Liver/pathology* ; Magnoliopsida/chemistry* ; Male ; Mice ; Mitochondria, Heart/drug effects* ; Mitochondria, Liver/drug effects* ; Myocardium/pathology* ; Plant Extracts/toxicity* ; Random Allocation

The ultrastructural alterations in rat liver by feeding NHM(nitrosohexamethylenemine). These are described at intervals of 10 days, 5 weeks, 11 weeks, 14 weeks, 19 weeks, and 22 weeks. The group at 5 and 11 weeks showed hyperplastic lesions but, no nuclear change. There were dilated rough endoplasmic reticulum with detached ribosomes, and alteration of mitochondria. The mitochondria showed a dense matrix which often included membranous materials. In the l4, 19, and 22 week groups, it showed nodular lesion which had atypical cells, and it was observed that the nucleus were enlarged and nucleoli were segregated. The bile canaliculi were dilated and contained dense materials.
Animal ; Female ; Liver/drug effects* ; Liver/pathology ; Methenamine/pharmacology* ; Microscopy, Electron ; Mitochondria, Liver/drug effects ; Nitrosamines/pharmacology ; Nitroso Compounds/pharmacology* ; Rats

Liver is the main place of drug metabolism. Mitochondria of hepatocytes are important targets of drug-induced liver injury. Mitochondrial autophagy could maintain the healthy operation of mitochondria in cells and the stable proliferation of cells. Therefore, the use of mitochondrial autophagy to remove damaged mitochondria is an important strategy of anti-drug-induced liver injury. Active ingredients that could enhance mitochondrial autophagy are contained in many traditional Chinese medicines, which could regulate the mitochondrial autophagy to alleviate relevant diseases. However, there are only a few reports on how to accurately and efficiently identify and evaluate such components targeting mitochondria from traditional Chinese medicine. Liquid chromatography-mass spectro-metry(LC-MS) combined with serum pharmacology in vivo can be used to accurately and efficiently find active ingredients of traditional Chinese medicine acting on mitochondrial targets. This paper reviewed the research ideas and methods of traditional Chinese medicine ingredients for increasing the hepatotoxicity of mitochondrial autophagy, in order to provide new ideas and methods for the study of active ingredients of traditional Chinese medicine targeting mitochondria.
Chemical and Drug Induced Liver Injury ; Drug-Related Side Effects and Adverse Reactions ; Drugs, Chinese Herbal/toxicity* ; Humans ; Medicine, Chinese Traditional ; Mitochondria

OBJECTIVETo demonstrate the effect of bromoxynil on membrane potential and respiratory control rate (RCR) in isolate mitochondria from mice liver tissue in vitro and the intervention of NAC.

METHODSThe mitochondrial was randomized to control group, bromoxynil-poisoned group and NAC-protected group. S3, S4 and RCR of the mitochondria in each sample was detected by the method of oxygen electrode. Each sample was stained by JC-1 and the changes of membrane potential of mitochondria were observed under fluorescence microscope.

RESULTSThe S3 [(0.031 +/- 0.008) nano atoms oxygen x mg(-1) x min(-1)], RCR (1.820 +/- 0.181) of bromoxynil-poisoned group and RCR (4.253 +/- 0.210) of NAC-protected group were significantly lower than those of control group (P<0.01); the S4 [(0.017 +/- 0.004) nano atoms oxygen x mg(-1) x min(-1)] of NAC-protected group was significantly higher than control group (P<0.01). The S3 [(0.046 +/- 0.005) nano atoms oxygen x mg(-1) x min(-1)] and RCR of NAC-protected group were significantly higher than group B (P<0.01), S4 [(0.011 +/- 0.001) nano atoms oxygen x mg(-1) x min(-1)] of NAC-protected group was significantly lower than bromoxynil-poisoned group (P< 0.01). Observation under fluorescence microscope: the red fluorescence of mitochondria was dim or disappeared in bromoxynil-poisoned group while brightened in NAC-protected group but still dimmer than control group.

CONCLUSIONIn vitro, the mitochondrial RCR and the mitochondrial membrane potential are decreased after the mitochondria is incubated with bromoxynil, and NAC could improve it.

Acetylcysteine ; pharmacology ; Animals ; Electron Transport ; drug effects ; Male ; Membrane Potential, Mitochondrial ; drug effects ; Mice ; Mice, Inbred ICR ; Mitochondria, Liver ; drug effects ; metabolism ; Nitriles ; toxicity

AIMTo investigate the mechanisms of anti-cancer effect of resveratrol (Res), and the effects of Res in cell apoptosis. The role of Res playing in mitochondrial permeability transition pore (PTP) induction was studied.

METHODSMitochondria was prepared from the liver of Wistar rats. The effects of Res on oxygen consumption of isolated mitochondria from rat liver was measured with Clark-type electrode and resulted in respiration control rate (RCR). Mitochondrial swelling affected by Res was assessed spectrophotometrically, through the changes in absorbance at 540 nm. The PTP opening was learned from the results. Membrane potential of mitochondia was measured through fluorescence spectrophotometry.

RESULTSRes was shown to inhibit the respiration and decrease the RCR of mitochondria. Res can promote the PTP opening mediated by Ca2+. Res was shown to promote the increase of mitochondial membrane potential mediated by Ca2+ and loss of mitochondial membrane potential.

CONCLUSIONRes was shown to inhibit mitochondial respiration and induce PTP opening of mitochondria. These may be one of the pathways that Res showed anti-cancer action and induce cells apoptosis.

Animals ; Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Calcium ; metabolism ; Female ; Ion Channels ; drug effects ; metabolism ; Membrane Potentials ; drug effects ; Mitochondria, Liver ; drug effects ; physiology ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Swelling ; drug effects ; Rats ; Rats, Wistar ; Stilbenes ; pharmacology

OBJECTIVETo observe the effects of silymarin on hepatic microsomal and mitochondrial membrane fluidity in mice.

METHODLiver microsomal and mitochondrial membranes were labled by ANS and DPH. Membrane fluorensent intensity (F), fluorensent polarization(P) and microviscosily(eta) of liver microsome and mitochondria were determined.

RESULTSil increased the external membrane fluidities of liver microsome and mitochondria, and decreased the internal membrane fluidities of liver microsome and mitochondria. Pretreatment with CCl4, the external membrane fluidity of liver microsome and mitochondria were increased, and the internal membrane fluidities of liver microsome and mitochondria were decreased. After given sil 140,280 mg.kg-1, the increased external membrane fluidities of liver microsome and mitochondria were lowered, and the decreased internal membrane fluidities of liver microsome and mitochondria were enhanced in a dose-dependent manner.

CONCLUSIONThe protective effects of sil on liver injury may be related to the recovery of the membrane fluidities of liver microsome and mitochondria.

Animals ; Carbon Tetrachloride Poisoning ; Liver Diseases ; etiology ; pathology ; Male ; Membrane Fluidity ; drug effects ; Mice ; Microsomes, Liver ; drug effects ; Milk Thistle ; chemistry ; Mitochondria, Liver ; drug effects ; Plants, Medicinal ; chemistry ; Protective Agents ; pharmacology ; Seeds ; chemistry ; Silymarin ; isolation & purification ; pharmacology

OBJECTIVETo investigate the effects of iron supplement on function of mitochondrial respiratory of liver during exercise-induced hypochromic rats.

METHODForty healthy male Wistar rats were randomized into 5 groups (n = 8): static control (C), exercise-training (T), training with supplementation of small dose iron (S + T), training with supplementation of middle dose iron (M + T) and training with supplementation of large dose iron (L + T). Training performed incremental exercise for 8 weeks, 6 days/week, iron supplementation from the fifth week. Liver were prepared immediately after exhaustive running. Liver mitochondria were extracted by differential centrifugation. Spectrophotometric analysis was used to evaluate activities of electron transport chain complex (C) I-IV in liver mitochondria.

RESULTS(1) C I, CII and CIV activities in T group were increased significantly (P < 0.05, P < 0.01), CI - C IV activities in S + T, M + T and L + T groups were increased significantly (P < 0.05, P < 0.01) compared with those in C group. (2) CII activity in S + T group was increased remarkably (P < 0.05); CIII and CIV activities in M + T group were increased remarkably (P < 0.01); CI - CIV activities in L+ T group were increased remarkably (P < 0.05, P < 0.01) compared with those in T group.

CONCLUSIONLarge load exercise training composite iron supplementation can improve function of mitochondrial respiration of liver and the aerobic capacity. From the athletic ability , the middle dose iron supplementation is better during large load exercise training.

Anemia, Hypochromic ; metabolism ; physiopathology ; Animals ; Cell Respiration ; drug effects ; Hemoglobins ; metabolism ; Iron ; administration & dosage ; pharmacology ; Male ; Mitochondria, Liver ; drug effects ; physiology ; Physical Conditioning, Animal ; Rats ; Rats, Wistar

OBJECTIVETo investigate the effects of resveratrol (Res) on mitochondrial opening and Ca(2+)-induced Ca(2+) release (CICR) from rat liver cell mitochondria mediated by Ca(2+).

METHODSWistar rat liver cell mitochondria was extracted and Res-induced mitochondrial swelling was assessed spectrophotometrically at 540 nm to examine the permeability transition pore (PTP) opening. The membrane potential changes of Res-treated mitochondria were measured with fluorescence spectrophotometery. Ca(2+) uptake and release by the mitochondria was determined by absorbance change of arsenazo III at 685-675 nm monitored by dual wavelength spectrophotometry.

RESULTSRes promoted Ca(2+)-mediated PTP opening, and this effect was completely inhibited by CsA and lowered by trifluoperazine. CICR accelerated by Res treatment was completely blocked by ruthenium red and partly by trifluoperazine.

CONCLUSIONRes can promote PTP opening by inducing CICR, which may be one of the pathways that Res induces cell apoptosis.

Animals ; Calcium ; metabolism ; Cells, Cultured ; Female ; Hepatocytes ; cytology ; metabolism ; Mitochondria, Liver ; drug effects ; metabolism ; Mitochondrial Membrane Transport Proteins ; metabolism ; Mitochondrial Swelling ; drug effects ; Rats ; Rats, Wistar ; Stilbenes ; pharmacology