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Vol. 289, Issue 2, 1176-1184, May 1999
Department of Drug Delivery Research, Graduate School of
Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
Four types of bovine liver catalase (CAT) derivatives, succinylated
(Suc-CAT), galactosylated (Gal-CAT), mannosylated (Man-CAT), and
polyethylene glycol conjugate (PEG-CAT), were synthesized and their
pharmacokinetics and therapeutic potential in a hepatic ischemia/reperfusion injury model were studied in mice. About 90% of
the CAT enzymatic activity was retained after chemical modification.
Biodistribution studies showed that 111indium
(111In)-Gal-CAT accumulated selectively in the liver
parenchymal cells as 111In-CAT, whereas an increased amount
of 111In-Suc-CAT and 111In-Man-CAT was
delivered to liver nonparenchymal cells. 111In-PEG-CAT
exhibited prolonged retention in plasma. Pharmacokinetic analysis
revealed that the hepatic uptake clearances of
111In-Suc-CAT, 111In-Gal-CAT, and
111In-Man-CAT were much greater than that of
111In-CAT, whereas that of 111In-PEG-CAT was
very small. In the ischemia/reperfusion injury model, in which hepatic
injury was induced by occlusion of the portal vein for 30 min followed
by 1 h reperfusion, the elevation of plasma glutamic pyruvic
transaminase and glutamic oxaloacetic transaminase levels was slightly
inhibited by treatment with native CAT or Gal-CAT. PEG-CAT was less
potent. In contrast, Suc-CAT and Man-CAT effectively suppressed the
increase in plasma glutamic pyruvic transaminase and glutamic
oxaloacetic transaminase. Coinjection of mannosylated superoxide
dismutase marginally improved the inhibitory effects of CAT
derivatives. These results demonstrate that targeted CAT delivery to
liver nonparenchymal cells via chemical modification is a promising
approach to prevent hepatic injuries caused by reactive oxygen species.
The potential usefulness of combining of CAT and superoxide dismutase
derivatives is also demonstrated.
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