Inhibition of ABCG2 prevents phototoxicity in a mouse model of erythropoietic protoporphyria

  • Nat Commun. 2024 Dec 4;15(1):10557. doi: 10.1038/s41467-024-54969-6.
Junjie Zhu  1 ,  Fu-Ying Qin  1 ,  Saifei Lei  1 ,  Ruizhi Gu  1 ,  Qian Qi  1 ,  Jie Lu  1 ,  Karl E Anderson  2 ,  Peter Wipf  3 ,  Xiaochao Ma  4
Affiliations
  • 1. Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
  • 2. Porphyria Laboratory & Center, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
  • 3. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4. Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
PMID: 39632884 DOI: 10.1038/s41467-024-54969-6
Abstract

Erythropoietic protoporphyria (EPP) is a genetic disease characterized by protoporphyrin IX-mediated painful phototoxicity. Currently, options for the management of EPP-associated phototoxicity are limited and no oral medication is available. Here, we investigated a novel therapy against EPP-associated phototoxicity by targeting the ATP-binding cassette subfamily G member 2 (ABCG2), the efflux transporter of protoporphyrin IX. Oral ABCG2 inhibitors were developed, and they successfully prevented EPP-associated phototoxicity in a genetically engineered EPP mouse model. Mechanistically, ABCG2 inhibitors suppress protoporphyrin IX release from erythroid cells and reduce the systemic exposure to protoporphyrin IX in EPP. In summary, our work establishes a novel strategy for EPP therapy by targeting ABCG2 and provides oral ABCG2 inhibitors that can effectively prevent protoporphyrin IX-mediated phototoxicity in mice.

Products