Enhancement of mitochondrial, cyanide-resistant superoxide dismutase in the livers of rats treated with 2,4-dinitrophenol.

Homogenates prepared from the livers of rats treated for 3 days with the uncoupling agent 2,4-dinitrophenol contained considerably higher cyanide-sensitive superoxide dismutase activity when compared with homogenates of saline-treated animals. The effect was specific for only one form of the enzyme, however. Administration of 2,4-dinitrophenol at a dosage and on a schedule which produced the classic signs of uncoupling of mitochondrial oxidative phosphorylation; that is, hyperthermia and weight loss, resulted in &fold increase in the liver mitochondrial, manganese superoxide dismutase but engendered no change in the cyanide-sensitive, cytosolic form of the enzyme. The ADP/O ratio for mitochondria prepared from dinitrophenol-treated animals was 2.0, whereas the ratio for mitochondria of saline-treated animals was 2.8. Hydrogen peroxide generation of mitochondria isolated from dinitrophenoltreated rats was 60 times higher than from mitochondria of saline-treated animals. Work from other laboratories has led to the conclusion that most, if not all, H202 generation from mitochondria reflects the production of the precursor, 0 2 . Although the specific source of 02is unknown, it appears reasonably certain that autoxidation of some reduced component of the mitochondrial electron transport chain is responsible. The enhanced oxygen radical generation with concomitant elevation of mitochondrial superoxide dismutase in livers of dinitrophenol-treated rats parallels the response observed in both neonatal rat pulmonary macrophages exposed to hyperoxia and microorganisms grown in the presence of chemicals which generate 0 2 by autoxidation. That the exposure of both prokaryotic and eukaryotic cells to a variety of conditions in which oxygen radical generation is enhanced is accompanied by an enhancement of superoxide dismutase, the enzyme which catalytically removes the Oz-, implies a fundamental association between the two processes.