ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIX-based photodynamic therapy.

SIGNIFICANCE STATEMENT This review summarized the roles of ABCG2 in modulating PPIX distribution and highlighted the therapeutic potential of ABCG2 inhibitors for the management of PPIX-mediated toxicity.

This work was supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01DK126875] (to X.M.).

X.M. and J.Z. are inventors on a patent (WO2020236901) and hold equity in Portal Therapeutics, Inc. K.E.A. reports receiving consulting fees, advisory board fees, and grants to the university from Alnylam Pharmaceuticals, Recordati Rare Diseases, Mitsubishi Tanabe Pharma America, and Disc Medicine.

dx.doi.org/10.1124/dmd.123.001582.