Toxic accumulation of protoporphyrin IX in the skin and liver of people with erythropoietic protoporphyria (EPP) — the most common porphyria of childhood — occurs through the action of the protein transporter ABCG2, a recent mouse study shows.
The findings suggest that blocking ABCG2 might be a way of treating EPP.
The study, “The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria,” was published in the journal Science Advances.
Erythropoietic protoporphyria (EPP) is caused by mutations in the FECH gene that carries the instructions to make the enzyme ferrochelatase. Lack of this enzyme leads to the toxic build-up of protoporphyrin IX (PPIX) in the blood, skin and liver.
Excessive PPIX in the skin of EPP patients causes extreme sensitivity to sunlight, and these people “must avoid light by decreasing outdoor activities and/or using protective clothing, which negatively affect their social and work activities and overall quality of life,” the researchers note. Current available therapies fail to address the root of EPP: the accumulation of PPIX in the skin.
PPIX is mainly produced in the bone marrow and released from red blood cells into the liquid part of the blood (plasma), through which it reaches organs like the skin. It is pumped from red blood cells by a single protein, called ABCG2, whose activity is promoted by light.
This evidence led researchers at the School of Pharmacy, University of Pittsburgh to hypothesize that suppressing ABCG2 would lessen the build-up of PPIX in the skin and ease phototoxicity in EPP. Since ABCG2 is also present in hepatocytes, the main cells of the liver, this approach might also ease the liver toxicity linked with PPIX accumulation.
They developed a mouse that lacked the ABCG2 gene and crossed it with a mouse model of EPP (carrying loss-of-function mutations in the FECH gene), which allowed them to investigate how ABCG2 protein deficiency impacts the animals’ response to light.
Results showed that mice defective in ABCG2 were protected from light-induced skin blisters compared to EPP mice (controls), which developed severe skin lesions upon exposure to light. Compared to control mice, the animals without ABCG2 also showed no signs of skin inflammation or oxidative stress following light exposure.
Researchers then measured the levels of PPIX and saw that lack of ABCG2 significantly increased its levels in red blood cells but reduced them in the plasma and skin. These findings strengthen the role of ABCG2 as the mediator of PPIX release into the blood and, eventually, the skin.
They also looked at PPIX accumulation in the livers of both groups of mice. Compared to EEP mice, animals lacking ABCG2 had significantly less PPIX accumulation in the liver and showed no signs of liver damage.
Overall, these data show that “ABCG2 is the key mediator in the pathophysiology [disease] of EPP, suggesting that ABCG2 is a potential target for EPP therapy,” the study concluded.