Molecular Pharmacology, Vol 20, 387-394, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Quinone-Stimulated Superoxide Formation by Subcellular Fractions, Isolated Hepatocytes, and Other Cells

¹ Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905

Quinones can undergo enzymatic one-electron reduction to the semiquinone radical which, in the presence of molecular oxygen, can transfer an electron and form the superoxide anion radical (O₂[unknown]). Isolated hepatocytes do not liberate appreciable amounts of O₂[unknown]. Simple quinones, such as 2,5-dimethyl-p-benzoquinone, stimulate the formation of O₂[unknown] by hepatocytes up to 15 nmoles/min/10⁶ cells. Hepatocyte O₂[unknown] formation stimulated by a variety of simple quinones and more complex antitumor quinones is maximal at a quinone one-electron reduction potential (E₇¹) of -70 mV and qualitatively similar to the pattern of O₂[unknown] formation seen with mitochondrial NADH:ubiquinone oxidoreductase and microsomal NADH-cytochrome b₅ reductase. O₂[unknown] production by microsomal NADPH-cytochrome P-450 reductase is maximal at a quinone E₇¹ of -200 mV. Phenobarbital induction, which increases NADPH-cytochrome P-450 reductase, has no effect on O₂[unknown]formation by hepatocytes. It is concluded that NADPH-cytochrome P-450 reductase activity is not rate-limiting for quinone-stimulated O₂[unknown] formation by hepatocytes. The sulfonated stilbenes, 4-acetamido-4'-isothiocyano-2,2'-disulfonic acid stilbene and 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene have no marked effect on the formation of O₂[unknown]by hepatocytes, suggesting that O₂[unknown] is not transported through anion channels in the plasma membrane. Ethanol has no effect on hepatocyte O₂[unknown] formation, which suggests that intracellular NADH is not rate-limiting. Treatment of hepatocytes with diethyldithiocarbamate, which inhibits cytosolic and mitochondrial superoxide dismutase, increases O₂[unknown] formation by hepatocytes over 2-fold. Feeding rats a copper-deficient diet, which also decreases hepatic cytosolic and mitochondrial superoxide dismutase, has no effect on the quinone-dependent formation of O₂[unknown] by hepatocytes.

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