Abstract
Reactive oxygen species have been postulated to underlie the pathogenesis of various diseases. Since these species rapidly react with various molecules, they should be scavenged appropriately at their site of generation. Superoxide dismutase (SOD) and related antioxidants have been expected to protect tissues from oxygen toxicity. However, because of their unfavorable pharmacokinetic properties, they often failed to inhibit oxidative tissue injury. In case of Cu/Zn-SOD, it disappeared from the circulation with a half-life of 5 min and underwent urinary excretion. Hence, intravenously administered SOD failes to dismutate superoxide radicals in vivo. The present work describes the chemical and genetic methods for targeting SOD to the site of generation and/or pathologic action of superoxide radical. Some SOD derivatives (SM-SOD, FA-SOD) reversibly bind to endogenous albumin thereby remain in the circulation with a half-life of 6 hr. Other derivatives (GSL-SOD, MAN-SOD, AH-SOD) selectively accumulate in hepatocytes, reticuloendothelial cells of liver, spleen and other tissues and renal proximal tubule cells, respectively. The fusion SOD (HB-SOD) preferentially binds to vascular endothelial cells thereby dismutates superoxide radicals in and around vascular walls. Pathophysiological role of superoxide and related free radicals, such as nitric oxide, were studied using these site-directed SODs.
