Targeting of superoxide dismutase to the liver results in anti-inflammatory effects in rats with fibrotic livers.
OBJECTIVE
The rapid clearance from plasma and the limited uptake of superoxide dismutase (SOD) in the liver hampers the effectiveness of this enzyme in liver diseases. We therefore compared the pharmacokinetics and in vivo efficacy of SOD with two modified forms of this protein: SOD coupled to the copolymer DIVEMA and mannosylated-SOD.


METHODS
Reactive oxygen scavenging activity of SOD conjugates was tested in livers of bile duct ligated rats. Intrahepatic production of reactive oxygen species (ROS) and neutrophil infiltration were studied immunohistochemically and related to the organ and cellular distribution of radiolabeled SOD conjugates.


RESULTS
Native SOD was rapidly cleared from the circulation and accumulated in renal tubuli. The enzyme had no effect on the intrahepatic ROS production. Covalent attachment of SOD to DIVEMA yielded a polyanionic conjugate with a prolonged elimination half-life compared to native SOD. In contrast to 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 cleared from the blood. This Man-SOD was taken up by non-parenchymal liver cells. 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 exhibited a potent inhibitory effect on ROS production in the liver. Nearly complete 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, application of DIVEMA-SOD seems a promising new approach to attenuate intrahepatic inflammatory processes.
Swart
P J
PJ
Groningen Utrecht Institute of Drug Exploration, Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, The Netherlands. swart.nl@yamanouchi-eu.com
Hirano
T
T
Kuipers
M E
ME
Ito
Y
Y
Smit
C
C
Hashida
M
M
Nishikawa
M
M
Beljaars
L
L
Meijer
D K
DK
Poelstra
K
K
D000818:Animals; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D020556:Neutrophil Infiltration; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000008:administration & dosage*
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase