Assessment of Hemoglobin-Dependent Neurotoxicity: Alpha-Alpha Crosslinked Hemoglobin

Panter, S. Scott; Vandegriff, Kim D.; Yan, Peiguang; Regan, Raymond F.

doi:10.3109/10731199409117870

Cited by 23 publications

(19 citation statements)

References 17 publications

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“…This finding is interestingly different to that reported for the interaction between 30 40 these proteins and hydrogen peroxide where the a-DBBF derivative consistently showed greater sensitivity to breakdown than HbAo [7,21]. It has recently been suggested that the cycling between the ferric and ferryl haem of a number of modified anges In the Soret region haemoglobins in the presence of hydrogen peroxide can result in tude changes upon carbon an apparent peroxidase activity and that this activity is sensitive to structural modifications of the protein [8,39]. Haemoglobin is also able to catalyse the oxidation of unsaturated fatty acids, such as phosphatidylcholine [40].…”

mentioning

confidence: 57%

Pro-oxidant effects of cross-linked haemoglobins explored using liposome and cytochrome c oxidase vesicle model membranes

Rogers

Patel

Reeder

et al. 1995

Biochemical Journal

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The therapeutic use of cell-free haemoglobin as a blood substitute has been hampered by toxicological effects. A model asolectin (phosphatidylcholine/phosphatidylethanolamine) liposome system was utilized to study the pro-oxidant efficiency of several chemically modified haemoglobins on biological membranes. Lipid peroxidation, resulting from the interactions between haemoglobin and liposomes, was measured by conjugated diene formation and the maximal rates of oxygen uptake. Spectral changes gave insight into the occurrence of the ferryl iron species. The residual reactivity of oxidatively damaged haemoglobins with ligands during incubation with liposomes was assessed from rapid kinetic carbon monoxide-binding experiments. Liposomes in which cytochrome c oxidase was embedded show both haemoglobin and the enzyme to be oxidatively damaged during incubation. The functional state of cytochrome c oxidase was monitored in the presence and absence of a free radical scavenger. Once in contact, both unmodified and modified haemoglobins triggered and maintained severe radical-mediated membrane damage. Differences in the pro-oxidant activities among haemoglobins may be explained by either the differential population of their ferryl intermediates or disparate dimerization and transfer of haem into the membrane with subsequent haem degradation. This study may contribute to a better understanding of the molecular determinants of haemoglobin interactions with a variety of biological membranes.

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mentioning

confidence: 57%

Pro-oxidant effects of cross-linked haemoglobins explored using liposome and cytochrome c oxidase vesicle model membranes

Rogers

Patel

Reeder

et al. 1995

Biochemical Journal

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“…Many, but not all, HBOCs are also bound by Hp, although the strength of binding varies, depending on the particular modifi cation chemistry utilized (Bunn 1967, Lockhart and Smith 1975, Benesch et al 1976, Panter et al 1994, Ship et al 2005, Schaer et al 2006, Buehler et al 2008, Baek et al 2012, Jia et al 2013. Th ese complexes are taken up by the liver, as are the much higher doses of free HBOC which are more representative of the anticipated clinical uses of these formulations (Bleeker et al 1989, Keipert et al 1989b, Smith et al 1990, Dittmer et al 1992, Hsia et al 1993, Bush et al 1994, Keipert et al 1994, Ship et al 2005, Baek et al 2012.…”

Section: Overview Of Distribution and Plasma Eliminationmentioning

confidence: 97%

Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

Estep¹

2015

Artificial Cells, Nanomedicine, and Biotechnology

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The circulatory persistence, distribution, and metabolism of hemoglobin-based oxygen carriers (HBOCs) is a major determinant of their safety and efficacy. In this communication, published data on the pharmacokinetics and routes of plasma elimination of HBOCs are summarized and evaluated. The circulating half-life of HBOCs is dose-dependent in both animals and humans. Half-life also increases with molecular weight in animals, at least up to the MDa range. The functional half-life of HBOCs is diminished by as much as 40% due to oxidation of the heme group relative to the overall rate of removal of hemoglobin (Hb) from plasma. Kidney excretion of HBOCs is greatly diminished compared to that of unmodified Hb, but the liver remains a primary site of catabolism. Both hepatocytes and Kupffer cells have been implicated in receptor-mediated HBOC uptake. Removal also occurs in the spleen and/or bone marrow and probably at dispersed sites in the endothelium as well. HBOCs extravasate into the lymph at a rate inversely proportional to their molecular weight and are taken up by monocyte/macrophage CD163 receptors, both as free Hb and in complexes with haptoglobin (Hp). The interactions with both Hp and the CD163 receptor are altered by Hb modification. However, monocyte/macrophage uptake may not be a quantitatively important route for the removal of clinically relevant doses of HBOCs. The relative contributions of different removal pathways have yet to be comprehensively determined, particularly in humans.

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“…Apart from low plasma levels of Hp and hemopexin, most Hb chemical modification procedures may decrease or eliminate the binding properties of Hb to Hp (19–21). Moreover, some chemical modification procedures, by altering Hb autoxidation kinetics and other related redox characteristics, may destabilize the heme‐globin binding force and increase the release of heme (22,23).…”

Section: Hemoglobin Clearancementioning

confidence: 99%

Intrinsic Toxicity of Hemoglobin: How to Counteract It

Simoni¹,

Simoni²,

Moeller³

2009

Artificial Organs

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The development of safe and effective blood substitutes is of great importance in both civilian and military medicine. The currently tested hemoglobin (Hb)-based oxygen carriers, however, have toxicity and efficacy problems. A number of unwanted effects have been observed in human trials, creating doubts about their clinical usefulness. In some subjects, vasoconstriction and decreased blood flow to the vital organs, heart attack, stroke, systemic inflammation, organ damage, and even death, have been attributed to the transfusion of these experimental products. Hb is a well-known pressor agent and strong oxidant, although the full understanding of its intrinsic toxicity is yet to be uncovered. In particular, the complete mechanism of Hb-induced vasoconstriction needs full elucidation. Knowledge of the biological events that trigger the induction of genes upon treatment with redox-active Hb, as well as its catabolism, is still incomplete. It seems that our limited knowledge of free Hb effects in vivo is the main reason for not yet having a viable substitute of human blood. The future for universal red cell substitutes is in the new-generation products that address all of Hb's intrinsic toxicity issues.

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Assessment of Hemoglobin-Dependent Neurotoxicity: Alpha-Alpha Crosslinked Hemoglobin

Cited by 23 publications

References 17 publications

Pro-oxidant effects of cross-linked haemoglobins explored using liposome and cytochrome c oxidase vesicle model membranes

Pro-oxidant effects of cross-linked haemoglobins explored using liposome and cytochrome c oxidase vesicle model membranes

Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

Intrinsic Toxicity of Hemoglobin: How to Counteract It

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