528 CHANCE, SIES,, AND BOVERIS Volume 59 measurement of the intracellular concentration of hydrogen peroxide, together with a better understanding of the experimental and theoretical basis for hydrogen peroxide generation and utilization in cells and tissues, now afford an appropriate background for a review of the physiological and biochemical aspects of intracellular hydroperoxide metabolism in mammalian systems. Although carbon monoxide-and cyanide-insensitive respiration, which bypasses the sequential reduction of oxygen via the respiratory carriers with the concomitant phosphorylation of ADP to ATP, has long been established, the physiological significance of a number of intermediates of oxygen reduction, produced in this or other intracellular reactions, has been recognized only in the last decade. This review focuses on hydrogen peroxide generation and utilization, emphasizing the function of catalase, the enzyme chiefly responsible for the intracellular regulation of H202. The reactions of glutathione peroxidase with H, O, and organic hydroperoxides are evaluated, as is the role of superoxide dismutase in converting the superoxide anion 02-to H202. The overall scheme of Figure 1, showing the interaction of these pathways, serves as the background for this study.