Superoxide dismutase, lipid peroxidation, and bell-shaped dose response curves.

Cellular metabolism generates the cytotoxic superoxide free radical, O(2).(-), and a family of enzymes called superoxide dismutases (SOD) protects us from O(2).(-) by catalyzing its conversion to O(2) and H(2)O(2). Superoxide production increases in a wide variety of pathological states, especially those involving inflammation or ischemic injury. Most of the literature has described systems wherein added or over expressed SOD produced beneficial effects, yet in some circumstances SOD provided no benefit, or was clearly detrimental, exacerbating cell injury or death. When broad dose-response studies were finally possible in models of reperfusion injury in the isolated heart, hormesis became clear. We propose that the mechanisms underlying the hormesis are related to the paradoxical abilities of the superoxide radical to serve as both an initiator and a terminator of the free radical-mediated chain reaction that results in lipid peroxidation. Lipid peroxidation is a universal feature of oxidative stress, causing loss of cellular structure and function. Under any given conditions, the optimal concentration of SOD is that which decreases chain initiation without elimination of the chain termination properties of the radical, resulting in a minimum of net lipid peroxidation. Mathematical modeling of this hypothesis yields predictions fully consistent with observed laboratory data.