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Comparison of the oxidative reactivity of recombinant fetal and adult human hemoglobin : implications for the design of hemoglobin-based oxygen carriers

Simons, Michelle; Gretton, Svetlana; Silkstone, Gary G.A.; Rajagopal, Badri S.; Allen-Baume, Victoria; Syrett, Natalie; Shaik, Thoufieq; Leiva-Eriksson, Nelida LU ; Ronda, Luca and Mozzarelli, Andrea, et al. (2018) In Bioscience Reports 38(4).
Abstract

Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing, in part due to the intrinsic oxidative toxicity of Hb. The most common HBOC starting material is adult human or bovine Hb. However, it has been suggested that fetal Hb may offer advantages due to decreased oxidative reactivity. Large-scale manufacturing of HBOC will likely and ultimately require recombinant sources of human proteins. We, therefore, directly compared the functional properties and oxidative reactivity of recombinant fetal (rHbF) and recombinant adult (rHbA) Hb. rHbA and rHbF produced similar yields of purified functional protein.... (More)

Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing, in part due to the intrinsic oxidative toxicity of Hb. The most common HBOC starting material is adult human or bovine Hb. However, it has been suggested that fetal Hb may offer advantages due to decreased oxidative reactivity. Large-scale manufacturing of HBOC will likely and ultimately require recombinant sources of human proteins. We, therefore, directly compared the functional properties and oxidative reactivity of recombinant fetal (rHbF) and recombinant adult (rHbA) Hb. rHbA and rHbF produced similar yields of purified functional protein. No differences were seen in the two proteins in: autoxidation rate; the rate of hydrogen peroxide reaction; NO scavenging dioxygenase activity; and the NO producing nitrite reductase activity. The rHbF protein was: less damaged by low levels of hydrogen peroxide; less damaging when added to human umbilical vein endothelial cells (HUVEC) in the ferric form; and had a slower rate of intrinsic heme loss. The rHbA protein was: more readily reducible by plasma antioxidants such as ascorbate in both the reactive ferryl and ferric states; less readily damaged by lipid peroxides; and less damaging to phosphatidylcholine liposomes. In conclusion in terms of oxidative reactivity, there are advantages and disadvantages to the use of rHbA or rHbF as the basis for an effective HBOC.

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Bioscience Reports
volume
38
issue
4
publisher
Kluwer
external identifiers
  • scopus:85049533095
ISSN
0144-8463
DOI
10.1042/BSR20180370
language
English
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yes
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8516f5d2-6137-4fca-84aa-7a65656836fb
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2018-07-23 11:01:12
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2018-09-16 04:56:20
@article{8516f5d2-6137-4fca-84aa-7a65656836fb,
  abstract     = {<p>Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing, in part due to the intrinsic oxidative toxicity of Hb. The most common HBOC starting material is adult human or bovine Hb. However, it has been suggested that fetal Hb may offer advantages due to decreased oxidative reactivity. Large-scale manufacturing of HBOC will likely and ultimately require recombinant sources of human proteins. We, therefore, directly compared the functional properties and oxidative reactivity of recombinant fetal (rHbF) and recombinant adult (rHbA) Hb. rHbA and rHbF produced similar yields of purified functional protein. No differences were seen in the two proteins in: autoxidation rate; the rate of hydrogen peroxide reaction; NO scavenging dioxygenase activity; and the NO producing nitrite reductase activity. The rHbF protein was: less damaged by low levels of hydrogen peroxide; less damaging when added to human umbilical vein endothelial cells (HUVEC) in the ferric form; and had a slower rate of intrinsic heme loss. The rHbA protein was: more readily reducible by plasma antioxidants such as ascorbate in both the reactive ferryl and ferric states; less readily damaged by lipid peroxides; and less damaging to phosphatidylcholine liposomes. In conclusion in terms of oxidative reactivity, there are advantages and disadvantages to the use of rHbA or rHbF as the basis for an effective HBOC.</p>},
  articleno    = {BSR20180370},
  author       = {Simons, Michelle and Gretton, Svetlana and Silkstone, Gary G.A. and Rajagopal, Badri S. and Allen-Baume, Victoria and Syrett, Natalie and Shaik, Thoufieq and Leiva-Eriksson, Nelida and Ronda, Luca and Mozzarelli, Andrea and Strader, Michael B. and Alayash, Abdu I. and Reeder, Brandon J. and Cooper, Chris E.},
  issn         = {0144-8463},
  language     = {eng},
  month        = {07},
  number       = {4},
  publisher    = {Kluwer},
  series       = {Bioscience Reports},
  title        = {Comparison of the oxidative reactivity of recombinant fetal and adult human hemoglobin : implications for the design of hemoglobin-based oxygen carriers},
  url          = {http://dx.doi.org/10.1042/BSR20180370},
  volume       = {38},
  year         = {2018},
}