ABSTRACT Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are two genetic diseases characterized by protoporphyrin IX (PPIX)-mediated phototoxicity and hepatotoxicity, and there is no cure. The objective of this project is to develop a mechanism-based strategy to manage PPIX-mediated toxicities. Our preliminary studies found that ABCG2, the efflux transporter of PPIX, plays an essential role in PPIX-mediated toxicities, and deficiency of ABCG2 abolishes such toxicities. Our further studies found that ABCG2 deficiency modulates PPIX distribution and metabolism. Based on these results, we hypothesize that suppression of ABCG2 will attenuate PPIX-mediated toxicities by modulating PPIX disposition. To test our hypothesis, we propose the following specific aims: (1) to develop ABCG2 inhibitors for the management of PPIX-mediated toxicities; (2) to determine the efficacy, safety, and mechanisms of action of these novel ABCG2 inhibitors for the prevention of PPIX-mediated phototoxicity; and (3) to determine the efficacy, safety, and mechanisms of action of ABCG2 inhibitors for the treatment of PPIX-mediated hepatotoxicity. We have successfully synthesized 28 ABCG2 inhibitors, and our preliminary data are promising because several of the tested candidates showed strong ABCG2 inhibitory activity and great efficacy against PPIX-mediated toxicities. In summary, this project will explore the therapeutic potential of ABCG2 inhibitors for the management of PPIX-mediated phototoxicity and hepatotoxicity. We will also illustrate the mechanisms by which suppression of ABCG2 attenuates PPIX- mediated toxicities. Genetically engineered ABCG2 and EPP mouse models together with ABCG2 inhibitors will be used in our proposed work. The results from this project will provide a novel strategy for the management of EPP and XLP.