Role of free radicals in the mechanism of the hydrazine-induced formation of megamitochondria.
The effect of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl(4-OH-TEMPO), a scavenger for free radicals, and 4-hydroxypyrazolo [3,4-d(pyrimidine)allopurinol], a xanthine oxidase inhibitor, on the hydrazine-induced changes of mitochondrial ultrastructure and those in the antioxidant system of the liver were investigated using rats as experimental animals. Animals were placed on a powdered diet containing 0.5% hydrazine for 7 d in the presence and absence of a combined treatment with 4-OH-TEMPO or allopurinol. Results obtained were as follows. 4-OH-TEMPO completely prevented the hydrazine-induced formation of megamitochondria in the liver, while it was partly prevented by allopurinol. The following changes observed in hydrazine-treated animals were improved almost completely by 4-OH-TEMPO:decreases in the body weight and liver weight; lowered rates of ADP-stimulated respiration and coupling efficiency of hepatic mitochondria; remarkable elevation of the level of lipid peroxidation. Improving effects of allopurinol were incomplete. The present results suggest that free radicals may play a key role in the mechanism of the hydrazine-induced formation of megamitochondria and that a part of free radicals generated during the hydrazine intoxication is ascribed to the degradation of purine nucleotides via xanthine oxidase. A general mechanism of the megamitochondria formation induced in various pathological conditions besides the case of hydrazine are discussed.
Matsuhashi
T
T
Department of Cell Biology and Molecular Pathology, Nagoya University School of Medicine, Japan.
Liu
X
X
Karbowski
M
M
Wozniak
M
M
Antosiewicz
J
J
Wakabayashi
T
T
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006834:Hydrazines / Q000633:toxicity*; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011687:Purines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013113:Spin Labels; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D005609:Free Radicals; D006834:Hydrazines; D011687:Purines; D017382:Reactive Oxygen Species; D013113:Spin Labels; C029424:hydrazine; D000493:Allopurinol; D044943:Fatty Acid Desaturases; D014969:Xanthine Oxidase; C001803:tempol