Dose- and Sex-Dependent Changes in Hemoglobin Oxygen Affinity by the Micronutrient 5-Hydroxymethylfurfural and α-Ketoglutaric Acid.

Astrid Ortner,Norbert Mair,Christopher Rugg,Hannes Gatterer,Marco Ronzani,Simon Woyke,Mathias Ströhle,Thomas Haller,Reinhold Wintersteiger

doi:10.3390/nu13103448

Abstract

5-Hydroxymethylfurfural (5-HMF) is known to increase hemoglobin oxygen affinity (Hb–O2 affinity) and to induce a left shift of the oxygen dissociation curve (ODC). It is under investigation as a therapeutic agent in sickle cell anemia and in conditions where pulmonary oxygen uptake is deteriorated or limited (e.g., various clinical conditions or altitude exposure). The combination of 5-HMF and α-ketoglutaric acid (αKG) is commercially available as a nutritional supplement. To further elucidate dose effects, ODCs were measured in vitro in venous whole blood samples of 20 healthy volunteers (10 female and 10 male) after the addition of three different doses of 5-HMF, αKG and the combination of both. Linear regression analysis revealed a strong dose-dependent increase in Hb–O2 affinity for 5-HMF (R2 = 0.887; p < 0.001) and the commercially available combination with αKG (R2 = 0.882; p < 0.001). αKG alone increased Hb–O2 affinity as well but to a lower extent. Both the combination (5-HMF + αKG) and 5-HMF alone exerted different P50 and Hill coefficient responses overall and between sexes, with more pronounced effects in females. With increasing Hb–O2 affinity, the sigmoidal shape of the ODC was better preserved by the combination of 5-HMF and αKG than by 5-HMF alone. Concerning the therapeutic effects of 5-HMF, this study emphasizes the importance of adequate dosing in various physiological and clinical conditions, where a left-shifted ODC might be beneficial. By preserving the sigmoidal shape of the ODC, the combination of 5-HMF and αKG at low (both sexes) and medium (males only) doses might be able to better maintain efficient oxygen transport, particularly by mitigating potentially deteriorated oxygen unloading in the tissue. However, expanding knowledge on the interaction between 5-HMF and Hb–O2 affinity in vitro necessitates further investigations in vivo to additionally assess pharmacokinetic mechanisms.

Highlights

The hemoglobin oxygen dissociation curve (ODC) characterizes the reversible binding of four molecules of oxygen to hemoglobin (Hb) [1]
The main parameters describing the ODC include the oxygen partial pressure at half saturation (P50) and the Hill coefficient (HC), with the latter depicting the maximum steepness of the ODC in the Hill plot and the cooperativity of the oxygen binding to Hb [2]
In healthy humans exposed to hypoxia as well as patients suffering from sickle cell anemia, Hb–O2 affinity was increased by 5-HMF [10,11]

Summary

Introduction

The hemoglobin oxygen dissociation curve (ODC) characterizes the reversible binding of four molecules of oxygen to hemoglobin (Hb) [1]. The micronutrient 5-HMF increases Hb–O2 affinity by way of allosteric modification of the Hb molecule by creating a Schiff-base adduct after transversing the red blood cell membrane [7,8]. In pigs exposed to hypoxia, 5-HMF increased Hb–O2 affinity, which led to an improved arterial oxygen saturation (SO2) and mitigated the hypoxia related increase in pulmonary arterial pressure [9]. In healthy humans exposed to hypoxia as well as patients suffering from sickle cell anemia, Hb–O2 affinity was increased by 5-HMF [10,11]. Despite being a strong anion and hydrophilic, αKG is known to be rapidly transported across red blood cell membranes, where it can potentially affect Hb–O2 affinity [13,14]. A prospective randomized trial in lung cancer patients showed positive effects of 5-HMF and αKG (Sanopal®) supplementation on maximum oxygen consumption (VO2max) and hospitalization time after single lung ventilation during thoracic surgery [15]

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