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BlvrB was determined to be an important antioxidant in mature red blood cells and was especially helpful in preventing hemolytic anemia in G6PD-deficient mice in a recent study.

Biliverdin reductase B (BlvrB) is the fourth-most abundant enzyme in red blood cells (RBCs) and is also present in many other tissues. Existing literature on heme metabolism and bilirubin-related pathologies has predominantly focused on biliverdin reductase A (BlvrA) and the alpha isomers of biliverdin and bilirubin. However, the porphyrin molecule, a crucial component of heme, can generate distinct biliverdin isomers (alpha, beta, gamma, or delta) when subjected to chemically coupled oxidation. 

While BlvrA primarily converts porphyrin to biliverdin-alpha, BlvrB uniquely reduces non-alpha biliverdin isomers to their corresponding bilirubin isomers. Despite being abundantly present and evolutionarily conserved, BlvrB’s function has remained elusive, with its only known impact being a subtle effect on hematopoietic lineage fate. This study, which was shared at the 65th ASH Annual Meeting & Exposition, posited a hypothesis suggesting that BlvrB plays a crucial antioxidant role that becomes particularly important when other redundant antioxidant pathways are limited. 

Biliverdin Reductase B Acts as an Antioxidant in Mature RBCs 

To investigate their hypothesis, the researchers generated a novel BlvrB knockout mouse on a C57BL/6 background. They employed a murine model of primaquine (PQ)-induced oxidative hemolytic anemia in mice deficient in glucose-6-phosphate dehydrogenase (G6PD), representing a clinically relevant scenario with compromised antioxidant biology leading to treatment-limiting pharmacotoxicity in RBCs.

Analysis of Murine Model Confirmed the Hypothesis

The study involved crossing BlvrB-knockout mice with two strains of mice carrying either the A-deficient variant of human G6PD (hG6PD(A-)) or the non-deficient form of human G6PD (hG6PD(ND)). Four distinct mouse strains, including hG6PD(ND) and hG6PD(A-) mice with or without BlvrB deletion, were subjected to either PQ treatment or control PBS injections, with anemia monitored through hematocrit (HCT) and reticulocyte count (RET) analysis. Additionally, high-resolution metabolomics was employed to detect biochemical changes in peripheral blood. 

Results revealed that PQ-induced hemolytic anemia in hG6PD(A-) mice and BlvrB deletion significantly exacerbated this effect through increased oxidation. The mice lacking BlvrB and G6PD(A-) exhibited defective glycolysis, altered redox metabolism, and specific increases in hypoxanthine and sphingosine-1-phosphate (S1P). These findings point to BlvrB’s previously undescribed antioxidant role in RBCs, particularly in the context of oxidative stress induced by G6PD deficiency.

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The Bottom Line

In conclusion, the study significantly enhances our understanding of BlvrB’s functional significance, especially in mature RBCs, highlighting its potential as a crucial player in antioxidant defense mechanisms. The observed exacerbation of oxidative injury in the absence of BlvrB suggests its involvement in safeguarding against oxidative stress, emphasizing its relevance to a large population affected by G6PD deficiency. 


Zimring, J. (2023, December 10). Biliverdin reductase B protects against primaquine induced hemolysis – identification of a novel Anti-Oxidant pathway in murine erythrocytes. https://ash.confex.com/ash/2023/webprogram/Paper178655.html