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Blood Cells Mol Dis. 2011 Oct 15;47(3):176-81. doi: 10.1016/j.bcmd.2011.07.003. Epub 2011 Aug 11.

Development of a novel mouse model of severe glucose-6-phosphate dehydrogenase (G6PD)-deficiency for in vitro and in vivo assessment of hemolytic toxicity to red blood cells.

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  • 1Institute of Chinese Medicine, Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China.

Abstract

Studies of hemolytic agents on G6PD-deficient subjects have been extensively performed on red blood cells obtained from donors, only using in vitro methods. However, there has been no adequate G6PD-deficient animal model for in vivo assessment of potentially hemolytic agents. The objective of this study is to establish a novel mouse model of severe G6PD-deficiency, with high susceptibility to hemolytic damage upon oxidative agents. To create this model, G6PD mutant Gpdx allele was introduced into the C57L/J mouse strain background by breeding program. The hemolytic toxicity of naphthalene and its metabolite α-naphthol on G6PD-deficient red blood cells was evaluated. Our data showed that the F2 homozygous Gpdx mutant with C57L/J background exhibiting the G6PD activity was 0.9±0.1 U/g Hb, level similar to those of G6PD deficiency in human. A significantly negative correlation was demonstrated between GSH percentage reduction and G6PD activity (r=-0.51, p<0.001) upon challenge of the red blood cells with alpha-naphthol in vitro. Similar correlation was also found between GSSG elevation and G6PD activity. Our in vivo studies showed that the administration of naphthalene at 250 mg/kg inflicted significant oxidative damage to the G6PD-deficient mice, as illustrated by the decrease of the GSH-to-GSSG ratio (by 34.2%, p=0.005) and the increase of the methemoglobin level (by 1.9 fold, p<0.001). Hemolytic anemia was also found in G6PD-deficient mice at this dosage of naphthalene. In summary, this novel mouse model could be utilized as a screening platform to more accurately determine the hemolytic toxicity of pharmacological agents on G6PD-deficient subjects.

PMID:
21839656
DOI:
10.1016/j.bcmd.2011.07.003
[PubMed - indexed for MEDLINE]
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