# The ABCG2 transporter in protoporphyrin IX disposition: from toxicity to therapy

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $340,014

## Abstract

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.

## Key facts

- **NIH application ID:** 10436376
- **Project number:** 5R01DK126875-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Xiaochao Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $340,014
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436376

## Citation

> US National Institutes of Health, RePORTER application 10436376, The ABCG2 transporter in protoporphyrin IX disposition: from toxicity to therapy (5R01DK126875-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436376. Licensed CC0.

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