Toxicity of Bilirubin and Detoxification by PEG-Bilirubin Oxidase Conjugate

A New Tactic for Treatment of Jaundice
  • Hiroshi Maeda
  • Masami Kimura
  • Ikuharu Sasaki
  • Yoshihiko Hirose
  • Toshimitsu Konno
Part of the Topics in Applied Chemistry book series (TAPP)


Bilirubin, the end product of heme catabolism, is generally regarded as toxic and highly fatal in newborn infants and fulminant hepatitis. Bilirubin encephalopathy (kernicterus) is usually considered to be caused by the entry of circulating, free (albumin-unbound), unconjugated bilirubin into the cerebral tissue.1,2 Bilirubin conjugation with glucuronic acid takes place in the liver and the process is impaired in liver diseases. Our tactic for the treatment of jaundice is to decompose toxic bilirubin by the enzyme bilirubin oxidase, and for that purpose the enzyme is made into a polymer conjugate to improve its pharmacological properties.3


Degradation Product Obstructive Jaundice Neonatal Jaundice Unconjugated Bilirubin Cyanuric Chloride 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    G. B. Odell, J. Clin. Invest. 38, 823 (1959).PubMedCrossRefGoogle Scholar
  2. 2.
    J. Bernstein and B. H. Landing, Am. J. Pathol. 40, 371 (1962).PubMedGoogle Scholar
  3. 3.
    M. Kimura, Y. Matsumura, Y. Miyauchi, and H. Maeda, Proc. Soc. Exp. Biol. Med. 188, 364 (1988).PubMedCrossRefGoogle Scholar
  4. 4.
    M. Kimura, Y. Matsumura, T. Konno, Y. Miyauchi, and H. Maeda, Proc. Soc. Exp. Biol. Med. 195, 64 (1990).PubMedCrossRefGoogle Scholar
  5. 5.
    R. Zeterstrom and L. Ernster, Nature 15, 1335 (1956).CrossRefGoogle Scholar
  6. 6.
    M. G. Mustafa, M. L. Cowger and T. E. King, Biochem. Biophys. Res. Commun. 29, 661 (1967).PubMedCrossRefGoogle Scholar
  7. 7.
    M. G. Mustafa, M. L. Cowger, and T. E. King, J. Biol. Chem. 244, 6463 (1969).Google Scholar
  8. 8.
    M. E. D. Notter and J. W. Kending, Exp. Neurol. 94, 670 (1986).PubMedCrossRefGoogle Scholar
  9. 9.
    L. F. Rasmussen and R. P. Wennberg, Res. Commun. Chem. Pathol. Pharmacol. 3, 567 (1972).PubMedGoogle Scholar
  10. 10.
    O. Schiff, G. Chan, and M. J. Poznansky, Pediatr Res. 19, 908 (1972).CrossRefGoogle Scholar
  11. 11.
    M. M. Thaler, Nat. New Biol. 230, 218 (1971).PubMedGoogle Scholar
  12. 12.
    M. L. Cowger, Biochem. Med. 5, 1 (1971).PubMedCrossRefGoogle Scholar
  13. 13.
    I. Miler, M. Indrova, J. Bubenik, and J. Vondracek, Folia Microbiol. (Praha) 30, 272 (1985).CrossRefGoogle Scholar
  14. 14.
    I. N. Dubin, B. Czernobilsky, and B. Herbst, Arch. Pathol. 79, 232 (1965).PubMedGoogle Scholar
  15. 15.
    R. Kaul, V. K. Bajpai, A. C. Shipstone, H. K. Kaul, and C. R. K. Murti, Exp. Mol. Pathol. 34, 290 (1981).PubMedCrossRefGoogle Scholar
  16. 16.
    C. L. Kapoor, C. R. Krishna-Murti, and P. C. Bajpai, Indian J. Med. Res. 60, 918 (1972).PubMedGoogle Scholar
  17. 17.
    S. O. Lie and D. Brantlid, Scand. J. Lab. Invest. 26, 37 (1970).CrossRefGoogle Scholar
  18. 18.
    S. Murao and N. Tanaka, Agric. Biol. Chem. 45, 2283 (1981).Google Scholar
  19. 19.
    S. Murao and N. Tanaka, Agric. Biol. Chem. 46, 2031 (1982).CrossRefGoogle Scholar
  20. 20.
    S. Murao and N. Tanaka, Agric. Biol. Chem. 46, 2499, 1982).CrossRefGoogle Scholar
  21. 21.
    N. Tanaka and S. Murao, Agric. Biol. Chem. 49, 843 (1985).CrossRefGoogle Scholar
  22. 22.
    C. Sung, A. Lavin, A. Klibanov, and R. Langer, Trans. Am. Soc. Artif. Internal Organs 31, 264 (1985).Google Scholar
  23. 23.
    A. Lavin, C. Sung, A. M. Klibanov, and R. Langer, Science 230, 543 (1985).PubMedCrossRefGoogle Scholar
  24. 24.
    H. Maeda, T. Matsumoto, T. Konno, K. Iwai, and M. Ueda, J. Protein Chem. 3, 181 (1984).CrossRefGoogle Scholar
  25. 25.
    H. Maeda, M. Ueda, T. Morinaga, and T. Matsumoto, J. Med. Chem. 28, 455 (1985).PubMedCrossRefGoogle Scholar
  26. 26.
    Y. Kamisaki, H. Wada, T. Yagura, A. Matsushita, and Y. Inada, J. Pharmacol. Exp. Ther. 216, 410 (1981).PubMedGoogle Scholar
  27. 27.
    Y. Ashihara, T. Kono, S. Yamazaki, and Y. Inada, Biochem. Biophys. Res. Commun. 83, 385 (1987).CrossRefGoogle Scholar
  28. 28.
    P S. Pyatak, A. Abuchowski, and F. F. Davis, Res. Comm. Chem. Pathol. Pharmacol. 29, 113–127 (1980).Google Scholar
  29. 29.
    M. S. Hershfield, R. H. Buckley, M. L. Greenberg, A. L. Melton, R. Schiff, C. Hatem, J. Kurzberg, M. L. Markert, R. H. Kobayashi, A. L. Kobayashi, and A. Abuchowski. N. Engl. J. Med. 316, 589 (1987).PubMedCrossRefGoogle Scholar
  30. 30.
    N. V. Katre, M. J. Knauf, and W. J. Laird, Proc. Natl. Acad. Sci. U.S.A. 84, 1487 (1987).PubMedCrossRefGoogle Scholar
  31. 31.
    K. Sugita, T. Sato, A. Fuse, and H. Nakajima, Biol. Neonate 49, 255 (1986).PubMedCrossRefGoogle Scholar
  32. 32.
    H. Tsuda, H. Maeda, and S. Kishimoto, Br. J. Cancer 43, 793 (1981).PubMedCrossRefGoogle Scholar
  33. 33.
    F. M. Veronase, R. Largajolli, E. Boccu, C. A. Benassi, and O. Schiavon, Appl. Biochem. Biotech. 11, 141 (1985).CrossRefGoogle Scholar
  34. 34.
    D. J. Hanatowich, W. W. Layne, and R. L. Childs, Int. J. Appl. Radiat. Isot. 33, 327 (1982).CrossRefGoogle Scholar
  35. 35.
    J. J. Munoz, Methods Immunol. Immunochem. 3, 146 (1970).Google Scholar
  36. 36.
    I. Diamond, and R. Schmid, J. Clin. Invest. 45, 678 (1966).PubMedCrossRefGoogle Scholar
  37. 37.
    R. Broderson, J. Pediatrics 96, 349 (1980).CrossRefGoogle Scholar
  38. 38.
    S. O. Lie and D. Brantlid, J. Scand. Lab. Invest. 26, 37 (1970).CrossRefGoogle Scholar
  39. 39.
    C. S. Simionatto, K. E. Anderson, G. S. Drummond, and A. Kappas, J. Clin. Invest. 75, 513 (1985).PubMedCrossRefGoogle Scholar
  40. 40.
    J. L. Golan, K. J. C. Dallinger, and B. Billing, Clin. Sci. Mol. Med. 54, 381 (1978).Google Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Hiroshi Maeda
    • 1
  • Masami Kimura
    • 1
  • Ikuharu Sasaki
    • 2
  • Yoshihiko Hirose
    • 2
  • Toshimitsu Konno
    • 1
  1. 1.Kumamoto University Medical SchoolKumamoto 860Japan
  2. 2.Amano Pharmaceutical Co., Ltd.Nagoya 481Japan

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