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As tert-butyl hydroperoxide is metabolized by the glutatione peroxidase--glutathione reductase enzyme system present in liver mitochondria, rapid and extensive oxidation of NADH and slow NADPH oxidation are observed. This NAD(P)H oxidation can be prevented, or reversed, more effectively by 2-hydroxybutyrate than by isocitrate, indicating an important role of mitochondrial NAD(P)+ transhydrogenase activity in maintaining a high NADPH/NADP+ ratio for glutathione reductase. In Ca2+-loaded mitochondria tert-butyl hydroperoxide-induced NAD(P)H oxidation is followed by Ca2+ release from the mitochondria. If either 2-hydroxybutyrate or isocitrate is present, no Ca2+ release can be induced by the hydroperoxide. Following Ca2+ efflux the NAD(P)H oxidation process becomes irreversible and membrane damage occurs. These late effects do not take place if ruthenium red is added to prevent re-uptake of released Ca2+ by the mitochondria. Thus, we conclude that the metabolism of tert-butyl hydroperoxide leads to a release of mitochondrial Ca2+ via oxidation of pyridine nucleotides, and that subsequent membrane damage is not directly associated with this Ca2+ efflux but results from continued cycling of released Ca2+.
Bellomo et al. (Sun,) studied this question.