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Mechanisms of G6PD-deficient RBC hemolysis mediated by oxidizing drugs328 views
Author
Dziewulska-Cronk, Karolina, Experimental Pathology - School of Medicine, University of Virginia0000-0001-8379-2004
Advisors
Zimring, James, Pathology, University of Virginia
Cross, Janet, MD-DMED Graduate Programs, University of Virginia
Goldfarb, Adam, Pathology, University of Virginia
Leitinger, Norbert, MD-PHAR Pharmacology, University of Virginia
Luckey, Chance, Pathology, University of Virginia
D'Alessandro, Angelo, Biochemistry and Molecular Biology, University of Colorado
Abstract
According to estimates by the World Health Organization, around 250 million people contract Plasmodium spp. worldwide every year. While drugs that can radically cure vivax malaria (i.e., primaquine and tafenoquine) are available, they are amongst numerous medicines like dapsone that are known to cause potentially life-threatening hemolytic sequelae in patients with G6PD deficiency and are thus contraindicated for use in patients with this most common human enzymopathy. As G6PD-deficient individuals account for approximately 5% of the entire global population, the inability to safely treat them results in both individual relapses and propagation of community-wide reinfection, hampering efforts to eradicate vivax malaria altogether. This dissertation describes the generation of a matched set of mice bearing humanized G6PD with either Mediterranean-deficient variant (hG6PDMed-), African-deficient variant (hG6PDA-) or non-deficient human G6PD (hG6PDND), knocked into the murine G6pdx locus. Using this novel model, we demonstrate the first in vivo confirmation that G6PD protein and enzyme activity decrease as a function of RBC age and that younger RBCs are resistant to the main hemolytic metabolite of primaquine. We also show that primaquine metabolite-induced clearance of hG6PDMed- RBCs is unaltered in agammaglobulinemic mice, rejecting the prevailing theory of a requirement for antibody opsonization. Finally, we here characterize the biochemical, metabolic, and cellular bases of primaquine- and dapsone-induced damage to hG6PD RBCs as well as systemic primaquine toxicity. Together, these findings advance our mechanistic understanding of the drug-induced hemolysis of G6PD-deficient RBCs, which may guide future investigations relevant to human health and disease.
Dziewulska-Cronk, Karolina. Mechanisms of G6PD-deficient RBC hemolysis mediated by oxidizing drugs. University of Virginia, Experimental Pathology - School of Medicine, PHD (Doctor of Philosophy), 2023-11-28, https://doi.org/10.18130/0d26-dn17.
