Targeting of superoxide dismutase to the liver results in anti-inflammatory effects in rats with fibrotic livers

Background/Aims: The rapid clearance from plasma and the limited uptake of superoxide dismutase (SOD) in the liver hampers the effectiveness of this e nzyme in liver diseases. We therefore compared the pharmacokinetics and in vivo efficacy of SOD with two modified forms of this protein: SOD coupled t o the copolymer DIVEMA and mannosylated-SOD. Methods: Reactive oxygen scavenging activity of SOD conjugates was tested i n livers of bile duct ligated rats. Intrahepatic production of reactive oxy gen species (ROS) and neutrophil infiltration were studied immunohistochemi cally and related to the organ and cellular distribution of radiolabeled SO D conjugates. Results: Native SOD was rapidly cleared from the circulation and accumulate d in renal tubuli. The enzyme had no effect on the intrahepatic ROS product ion. Covalent attachment of SOD to DIVEMA yielded a polyanionic conjugate w ith a prolonged elimination half-life compared to native SOD, In contrast t o native SOD, DIVEMA-SOD was taken up by the liver via scavenger receptors. Mannosylation of SOD (Man-SOD) resulted in a conjugate that was rapidly cl eared from the blood. This Man-SOD was taken up by non-parenchymal liver ce lls. The pharmacokinetics of SOD and its derivatives were similar in normal and bile duct ligated rats. Efficacy studies with Man-SOD revealed only a slight decrease in intrahepatic ROS production. However, DIVEMA-SOD exhibit ed a potent inhibitory effect on ROS production in the liver. Nearly comple te ROS-scavenging activity was observed in the portal areas. Conclusions: Considering the prolonged half-life, the increased delivery of SOD to the target cells, and the concomitant increased effectiveness, appl ication of DIVEMA-SOD seems a promising new approach to attenuate intrahepa tic inflammatory processes.