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Research ArticleArticle

Targeted Delivery and Improved Therapeutic Potential of Catalase by Chemical Modification: Combination with Superoxide Dismutase Derivatives

Yoshiyuki Yabe, Makiya Nishikawa, Ayumi Tamada, Yoshinobu Takakura and Mitsuru Hashida
Journal of Pharmacology and Experimental Therapeutics May 1999, 289 (2) 1176-1184;
Yoshiyuki Yabe
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Makiya Nishikawa
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Ayumi Tamada
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Yoshinobu Takakura
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Mitsuru Hashida
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Abstract

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 of111In-Suc-CAT, 111In-Gal-CAT, and111In-Man-CAT were much greater than that of111In-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.

Footnotes

  • Send reprint requests to: Mitsuru Hashida, Ph.D., Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606 to 8501, Japan. E-mail: hashidam{at}pharm.kyoto-u.ac.jp

  • ↵1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan and the grant of “Basic Research on Drug Innovation” by the Japan Health Sciences Foundation.

  • Abbreviations:
    CAT
    catalase
    SOD
    superoxide dismutase
    ROS
    reactive oxygen species
    Suc-CAT
    succinylated CAT
    PEG-CAT
    CAT-polyethylene glycol conjugate
    Gal-CAT
    galactosylated CAT, Man-CAT, mannosylated CAT
    Gal-SOD
    galactosylated SOD
    Man-SOD
    mannosylated SOD
    BSA
    bovine serum albumin
    Suc-BSA
    succinylated BSA
    Man-BSA
    mannosylated BSA
    DTPA
    diethylenetriaminepentaacetic acid
    PC
    parenchymal cells
    NPC
    nonparenchymal cells
    AUC
    area under the plasma concentration-time curve
    CLtotal
    total body clearance
    CLorg
    organ uptake clearance
    CLliver
    hepatic uptake clearance
    CLkidney
    renal uptake clearance
    CLurine
    urinary excretion clearance
    GPT
    glutamic pyruvic transaminase
    GOT
    glutamic oxaloacetic transaminase
    TNBS
    trinitrobenzene sulfonic acid
    • Received September 8, 1998.
    • Accepted January 7, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 2
1 May 1999
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Research ArticleArticle

Targeted Delivery and Improved Therapeutic Potential of Catalase by Chemical Modification: Combination with Superoxide Dismutase Derivatives

Yoshiyuki Yabe, Makiya Nishikawa, Ayumi Tamada, Yoshinobu Takakura and Mitsuru Hashida
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 1176-1184;

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Research ArticleArticle

Targeted Delivery and Improved Therapeutic Potential of Catalase by Chemical Modification: Combination with Superoxide Dismutase Derivatives

Yoshiyuki Yabe, Makiya Nishikawa, Ayumi Tamada, Yoshinobu Takakura and Mitsuru Hashida
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 1176-1184;
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