Reduced Enzymic Control of Free Radical and electron transport reactions in the mitochondria of zajdela hepatoma ascitic cells: A model for the stepwise transformation of healthy to tumorous cells involving a progressive loss of antioxidant activity

Abstract

Differences in the radical chemistry of normal and tumorous rat liver cells were demonstrated using e.s.r. techniques. In healthy cells the one‐electron transfer from hemoproteins to peroxides and hydroperoxides is accompanied by radical formation and proceeds predominantly in the endoplasmatic reticulum. Their mitochondria are effectively shielded against autoxidation. The opposite is true for Zajdela hepatoma ascitic cells and mitochondria. Mitochondria isolated from this type of cancerous cell are sensitive targets for radical attack and irreversible oxidation of thier hemoproteins from the FeII to FeIII oxidative state. A probable location for electron leakage in cancerous rat liver cells, depleted of the enzyme Mn‐SOD, controlling the O 2− level, and of catalase, controlling the H2O2 level, seems to be the ubisemiquinone‐cytochrome c component of the mitochondrial respiration redox chain, where the active center of cytochrome oxidase is blocked and so the controlled four‐electron transfer to molecular oxygen is prevented. A model is proposed to explain the stepwise transformation of a highly organized differentiated cell to an uncontrolled proliferating tumor cell. The transition is brought about by a progressive loss of protective capacity which allows transition metal coordinated radicals, carried by hemoproteins, to cross the nuclear membrane. Inside the nucleus decomplexation of the stabilized radicals will release damaging short‐lived radical species.