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-TE MPO), a scavenger for free radicals, and 4-hydroxypyrazolo [3,4-d(pyri midine) allopurinol], a xanthine oxidase inhibitor, on the hydrazine-i nduced changes of mitochondrial ultrastructure and those in the antiox idant system of the liver were investigated using rats as experimental animals. Animals were placed on a powdered diet containing 0.5% hydra zine 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-TEMP O completely prevented the hydrazine-induced formation of megamitochon dria in the liver, while it was partly prevented by allopurinol. The f ollowing changes observed in hydrazine-treated animals were improved a lmost completely by 4-OH-TEMPO:decreases in the body weight and liver weight; lowered rates of ADP-stimulated respiration and coupling effic iency of hepatic mitochondria; remarkable elevation of the level of li pid peroxidation. Improving effects of allopurinol were incomplete. Th e present results suggest that free radicals may play a key role in th e mechanism of the hydrazine-induced formation of megamitochondria and that a part of free radicals generated during the hydrazine intoxicat ion is ascribed to the degradation of purine nucleotides via xanthine oxidase. A general mechanism of the megamitochondria formation induced in various pathologic conditions besides the case of hydrazine are di scussed. (C) 1997 Elsevier Science Inc.