Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties

Nature Biotechnology volume 16, pages 667–671 (1998)Cite this article

Abstract

Polyhemoglobin-superoxide dismutase-catalase is designed to function as an oxygen carrier with antioxidant properties. This is based on cross-linking hemoglobin with superoxide dismutase and cata-lase (PolyHb-SOD-CAT). This study describes the structural and antioxidant properties of this solution. Our studies show that superoxide dismutase and catalase retain their enzymatic activity following glu-taraldehyde polymerization with 8:1 and 16:1 glutaraldehyde:hemoglobin ratio. We have analyzed the optimal SOD/CAT ratios to prevent oxidation of hemoglobin in the presence of oxygen free radicals. The circulation half-life of crosslinked hemoglobin, SOD, and catalase in Sprague-Dawley rats correlates with the degree of polymerization as determined by high-performance molecular weight gel filtration. PolyHb-SOD-CAT decreases the formation of oxygen radicals compared with PolyHb in a rat intestinal ischemia-reperfusion model.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Chang, T.M.S. 1997. Blood substitutes: principles, methods, products and clinical trials, Vol. I. Karger, Basel, Switzerland.

    Google Scholar 

  2. Gould, S.A. and Moss, G.S. 1996. Clinical development of human polymerized hemoglobin as a blood substitute. World J. Surg. 20: 1200–1207.

    Article  CAS  Google Scholar 

  3. Chang, T.M.S. (ed.). 1998. Blood substitutes: principles, methods, products and clinical trials, Vol. II. Karger, Basel, Switzerland.

    Google Scholar 

  4. Winslow, P.M. 1996. Blood substitutes in development. Exp. Opin. Invest. 5: 1443–1452.

    Article  CAS  Google Scholar 

  5. Fransen, E.J., Maessen, J.G., Hermens, W.T., and Glatz, J.F. 1998. Demonstration of ischemia-reperfusion injury separate from postoperative infarction in coronary artery bypass graft patients. Ann. Thorac. Surg. 65: 48–53.

    Article  CAS  Google Scholar 

  6. Bowler, J.V., Wade, J.P., Jones, B.E., Nijran, K.S., and Steiner, T.J. 1998. Natural history of the spontaneous reperfusion of human cerebral infarcts as assessed by 99mTc HMPAO SPECT. J. Neurol. Neurosurg. Psychiatry 64: 90–97.

    Article  CAS  Google Scholar 

  7. Serraf, A., Robotin, M., Bonnet, N., Detruit, H., Baudet, B., Mazmanian, M.G. et al. 1997. Alteration of the neonatal pulmonary physiology after total cardiopul-monary bypass. J. Thorac. Cardiovasc. Surg. 114: 1061–1069.

    Article  CAS  Google Scholar 

  8. Shah, K.A., Shurey, S., and Green, C.J. 1997. Apoptosis after intestinal ischemiareperfusion injury: a morphological study. Transplantation 64: 1393–1397.

    Article  CAS  Google Scholar 

  9. Kundu, S., Herman, S.J., and Winton, T.L. 1998. Reperfusion edema after lung transplantation: radiographic manifestations. Radiology 206: 75–80.

    Article  CAS  Google Scholar 

  10. Mueller, A.R., Platz, K.P., Schumacher, G., Riger, J., Gebauer, B., Neumann, U., and Neuhaus, P. 1997. Mechanisms of preservation and reperfusion injury in human liver transplantation. Transplant Proc. 29: 3455–3457.

    Article  CAS  Google Scholar 

  11. Granger, D.N. and Korthius, R.J. 1995. Physiologic mechanisms of postischemic tissue injury. Annu. Rev. Physiol. 57: 311–332.

    Article  CAS  Google Scholar 

  12. McCord, J.M. 1993. Human disease, free radicals, and the oxidant/antioxidant balance. Clin. Biochem. 26: 351–357.

    Article  CAS  Google Scholar 

  13. Reilly, P.M., Schiller, H.J., and Bulkley, G.B. 1991. Pharmacologic approach to tissue injury mediated by free radicals and other reactive oxygen metabolites. Am. J. Surg. 161: 488–503.

    Article  CAS  Google Scholar 

  14. Rice-Evans, C.A. and Diplock, A.T. 1990. Current status of antioxidant therapy. Free Radic. Biol. Mod. 15: 77–96.

    Article  Google Scholar 

  15. Greenwald, R.A. 1990. Superoxide dismutase and catalase as therapeutic agents for human diseases: a critical review. Free Radio. Biol. Med. 8: 201–209.

    Article  CAS  Google Scholar 

  16. D'Agnillo, F. and Chang, T.M.S. 1997. Hemoglobin-enzyme complexes. U.S. 5,606,025.

    Google Scholar 

  17. D'Agnillo, F. and Chang, T.M.S. 1993. Crosslinked hemoglobin-superoxide dis-mutase-catalase scavenges oxygen-derived free radicals and prevents methe-moglobin formation and iron release. Biomaterials, Artificial Cells, and Artificial Organs 21: 609–621.

    CAS  Google Scholar 

  18. Everse, J. and Hsia, N. 1997. The toxicities of native and modified hemoglobins. FreeRadic. Biol. Med. 22: 1075–1099.

    Article  CAS  Google Scholar 

  19. Chang, T.M.S. and Daka, J. 1989. Removal of bilirubin by the pseudoperoxidase activity of immobilized hemoglobin. U.S. 4820416.

    Google Scholar 

  20. Razack, S., D'Agnillo, F. and Chang, T.M.S. 1997. Crosslinked hemoglobin-superoxide dismutase-catalase scavenges free radicals in a rat model of intestinal ischemia-reperfusion. Artif. Cells Blood Substit, Immobil. Biotechnol. 25: 181–192.

    Article  CAS  Google Scholar 

  21. D'Agnillo, F. and Chang, T.M.S. 1998. Absence of hemoprotein-associated free radical events following oxidant challenge of Crosslinked hemoglobin-superoxide dismutase-catalase. Free Radio. Biol. Med. 24: 906–912.

    Article  CAS  Google Scholar 

  22. Guillochon, D., Vijayalakshmi, M.W., Thiam-Sow, A., and Thomas, D. 1986. Effect of glutaraldehyde on hemoglobin: functional aspects and Mossbauer parameters. Biochem. Cell Biol. 64: 29–37.

    Article  CAS  Google Scholar 

  23. Quebec, E.A. and Chang, T.M.S. 1995. Superoxide dismutase and catalase Crosslinked to polyhemoglobin reduces methemoglobin formation in vitro. Artif. Cells Blood Substit. Immobil. Biotechnol. 23: 693–705.

    Article  CAS  Google Scholar 

  24. Olson, J.S., Ballow, D.P., Palmer, G., and Massey, V. 1974. The reaction of xanthine oxidase with molecular oxygen. J. Biol. Chem. 249: 4350–62.

    CAS  PubMed  Google Scholar 

  25. Li, G.K., Chen, Y., Saan, J.T., and Kang, Y.J. 1997. Catalase-overexpressing transgenic mouse heart is resistant to ischemia-reperfusion injury. Am. J. Physiol. 273: H1090–H1095.

    CAS  PubMed  Google Scholar 

  26. Wu, S., Nagashima, T., Ikeda, K., Kondoh, T., Yamaguchi, M., and Tamaki, N. 1997. The mechanism of free radical generation in brain capillary endothelial cells after anoxia and reoxygenation. Acta Neurochir. Suppl. 70: 37–39.

    CAS  PubMed  Google Scholar 

  27. Jourd'heuil, D., Mills, L., Miles, A.M., and Grisham, M.B. 1998. Effect of nitric oxide on hemoprotein-catalyzed oxidative reactions, pp. 37–44 in Nitric oxide: biology and chemistry, Vol. 2. Academic Press, San Diego, CA.

    Google Scholar 

  28. Alayash, A.I., Ryan, B.A., and Cashon, R.E. 1998. Peroxynitritemediated heme oxidation and protein modification of native and chemically modified hemoglobins. Arch. Biochem. Biophys. 349 65–73.

    Article  CAS  Google Scholar 

  29. Beckman, J.S. and Koppenol, W.H. 1996. Nitric oxide, Superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 271: C1424–C1437.

    Article  CAS  Google Scholar 

  30. Wang, P. and Zweier, J.L. 1996. Measurement of nitric oxide and peroxynitrite generation in the postischemic heart. Evidence for peroxynitrite-mediated reperfusion injury. J. Biol. Chem. 271: 29223–29230.

    Article  CAS  Google Scholar 

  31. Tosaki, A., Bagchi, D., Pali, T., Cordis, G.A., and Das, O.K. 1993. Comparisons of ESR and HPLC methods for the detection of OH radicals in ischemic/reperfused hearts. Biochem. Pharmocol. 45: 961–969.

    Article  CAS  Google Scholar 

  32. Pollak, R., Andreisevic, J.H., Maddux, M.S., Gruber, S.A., and Paller, M.S. 1993. A randomized double-blind trial of the use of human recombinant superoxide dismutase in renal transplantation. Transplantation 55: 57–60.

    Article  CAS  Google Scholar 

  33. Bernier, M., Manning, A.S., and Hearse, D J. 1989. Reperfusion arrhythmias: dose-related protection by anti-free radical interventions. Am. J. Physiol. 256: H1344–H1352.

    CAS  PubMed  Google Scholar 

  34. Drabkin, D.L. and Austin, J.H. 1935. J. Biol. Chem. 112: 51.

    CAS  Google Scholar 

  35. Flothé, L. and Ötting, F. 1984. Superoxide dismutase assays. Methods Enzymol. 105: 93–104.

    Article  Google Scholar 

  36. Aebi, H. 1984. Catalase in vitro. Methods Enzymol. 105: 121–126.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Thomas M.S. Chang

    Present address: Laboratory of Cellular Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, 20892

Authors and Affiliations

  1. Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, PQ, Canada

    Felice D'Agnillo

Authors
  1. Felice D'Agnillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas M.S. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas M.S. Chang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

D'Agnillo, F., Chang, T. Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties. Nat Biotechnol 16, 667–671 (1998). https://doi.org/10.1038/nbt0798-667

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt0798-667

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing