Effects of GlyT1 inhibition on erythropoiesis and iron homeostasis in rats

Winter, Michael; Funk, Jürgen; Körner, Annette; Alberati, Daniela; Christen, François; Schmitt, Georg; Altmann, Bernd; Pospischil, Andreas; Singer, Thomas P.

doi:10.1016/j.exphem.2016.07.003

Cited by 21 publications

(19 citation statements)

References 42 publications

(45 reference statements)

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“…Taken together, these results indicate that bitopertin ameliorates anemia of Hbb th3/+ mice. WT mice showed hematologic changes similar to those previously reported in healthy rats, with the appearance of mild hypochromic microcytic erythrocytes in the absence of anemia (20).…”

Section: Resultssupporting

confidence: 83%

“…Bitopertin is an oral selective inhibitor of GlyT1 that was originally developed to treat negative symptoms of patients with schizophrenia (20)(21)(22)(23). Although efficacy of bitopertin in schizophrenia could not be proved in several randomized, double-blind, placebo-controlled, phase III trials, a dose-dependent microcytic hypochromic erythropoiesis with reduction in hemoglobin (Hb) values was consistently observed in bitopertin-treated subjects.…”

Section: Introductionmentioning

confidence: 99%

“…Although efficacy of bitopertin in schizophrenia could not be proved in several randomized, double-blind, placebo-controlled, phase III trials, a dose-dependent microcytic hypochromic erythropoiesis with reduction in hemoglobin (Hb) values was consistently observed in bitopertin-treated subjects. This indicated the ability of bitopertin to inhibit GlyT1-mediated glycine transport during normal erythropoiesis, generating a "heme-restricted" environment (20,21). Heme-sensing HRI has been shown to be responsible for microcytic hypochromic anemia of iron deficiency (10).…”

Section: Introductionmentioning

confidence: 99%

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Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

Federti¹,

Winter²,

Koerner³

et al. 2019

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

Federti¹,

Winter²,

Koerner³

et al. 2019

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“…During the preparation of our study for publication, bitopertin was reported to cause anemia in rats. 49 Similarly to what we observed in GlyT1 −/− newborn mice ( Table 1 ), adult rats treated with bitopertin showed decreases in mean corpuscular volume, mean corpuscular hemoglobin and hemoglobin levels, when compared to those of controls. 49 Additionally, as expected, bitopertin administration led to an increase in erythropoietin levels in rats.…”

Section: Discussionsupporting

confidence: 83%

“… 49 Similarly to what we observed in GlyT1 −/− newborn mice ( Table 1 ), adult rats treated with bitopertin showed decreases in mean corpuscular volume, mean corpuscular hemoglobin and hemoglobin levels, when compared to those of controls. 49 Additionally, as expected, bitopertin administration led to an increase in erythropoietin levels in rats. 49 Our study, for the first time, presents compelling evidence that glycine uptake by erythroblasts represents a limiting step in heme and, consequently, hemoglobin production ( Figures 2 and 3 ).…”

Section: Discussionsupporting

confidence: 83%

Extracellular glycine is necessary for optimal hemoglobinization of erythroid cells

et al. 2017

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Vertebrate heme synthesis requires three substrates: succinyl-CoA, which regenerates in the tricarboxylic acid cycle, iron and glycine. For each heme molecule synthesized, one atom of iron and eight molecules of glycine are needed. Inadequate delivery of iron to immature erythroid cells leads to a decreased production of heme, but virtually nothing is known about the consequence of an insufficient supply of extracellular glycine on the process of hemoglobinization. To address this issue, we exploited mice in which the gene encoding glycine transporter 1 (GlyT1) was disrupted. Primary erythroid cells isolated from fetal livers of GlyT1 knockout (GlyT1 −/− ) and GlyT1-haplodeficient (GlyT1 +/− ) embryos had decreased cellular uptake of [2 −14 C]glycine and heme synthesis as revealed by a considerable decrease in [2- 14 C]glycine and 59 Fe incorporation into heme. Since GlyT1 −/− mice die during the first postnatal day, we analyzed blood parameters of newborn pups and found that GlyT1 −/− animals develop hypochromic microcytic anemia. Our finding that Glyt1-deficiency causes decreased heme synthesis in erythroblasts is unexpected, since glycine is a non-essential amino acid. It also suggests that GlyT1 represents a limiting step in heme and, consequently, hemoglobin production.

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