Erythropoietic protoporphyria: Evidence that it is due to a variant ferrochelatase

et al. 2019

Sci. Adv.

Erythropoietic protoporphyria (EPP) is an inherited disease caused by loss-of-function mutations of ferrochelatase, an enzyme in the heme biosynthesis pathway that converts protoporphyrin IX (PPIX) into heme. PPIX accumulation in patients with EPP leads to phototoxicity and hepatotoxicity, and there is no cure. Here, we demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity. We found that ABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents EPP-associated phototoxicity. We also found that ABCG2 deficiency protects against EPP-associated hepatotoxicity by modulating PPIX distribution, metabolism, and excretion. In summary, our work has uncovered an essential role of ABCG2 in the pathophysiology of EPP, which suggests the potential for novel strategies in the development of therapy for EPP.

Section: Introductionmentioning

confidence: 99%

The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria

Wang

et al. 2019

Sci. Adv.

“…Erythropoietic protoporphyria (EPP) is the third most common type of porphyria, and usually first diagnosed in early childhood [1]. EPP results from the defective mutation of the gene encoding ferrochelatase (FECH), the enzyme that is responsible for the final step of heme synthesis [2–4]. FECH catalyzes the insertion of a ferrous iron into protoporphyrin IX (PPIX) to form heme, which mainly occurs in the bone marrow and liver [2, 5, 6].…”

Section: Introductionmentioning

confidence: 99%

Liver metabolomics in a mouse model of erythropoietic protoporphyria

Wang

Biochemical Pharmacology

Guo

et al. 2018

Erythropoietic protoporphyria (EPP) is a genetic disease that results from the defective mutation in the gene encoding ferrochelatase (FECH), the enzyme that converts protoporphyrin IX (PPIX) to heme. Liver injury and even liver failure can occur in EPP patients because of PPIX accumulation in the liver. The current study profiled the liver metabolome in an EPP mouse model caused by a Fech mutation (Fech-mut). As expected, we observed the accumulation of PPIX in the liver of Fech-mut mice. In addition, our metabolomic analysis revealed the accumulation of bile acids and ceramide (Cer) in the liver of Fech-mut mice. High levels of bile acids and Cer are toxic to the liver. Furthermore, we found that the major phosphatidylcholines (PC) in the liver and the ratio of total PC to PPIX in the bile were decreased in Fech-mut mice compared to wild type mice. A decrease of the ratio of PC to PPIX in the bile can potentiate the accumulation of PPIX in the liver because PC increases PPIX solubility and excretion. These metabolomic findings suggest that the accumulation of PPIX, together with the disruption of the homeostasis of bile acids, Cer, and PC, contributes to EPP-associated liver injury.

“…Thus, GSF treatment in mice causes PPIX accumulation in the liver which leads to liver damage [7, 8]. This phenotype is similar to human subjects with erythropoietic protoporphyria (EPP)-associated liver injury [7, 11, 12]. Therefore, GSF is commonly used as a tool drug to generate a mouse model for investigating EPP-associated liver injury [7, 8].…”

Section: Introductionmentioning

confidence: 99%

A metabolomic perspective of griseofulvin-induced liver injury in mice

Liu

Yan

Biochemical Pharmacology

et al. 2015

Griseofulvin (GSF) causes hepatic porphyria in mice, which mimics the liver injury associated with erythropoietic protoporphyria (EPP) in humans. The current study investigated the biochemical basis of GSF-induced liver injury in mice using a metabolimic approach. GSF treatment in mice resulted in significant accumulations of protoporphyrin IX (PPIX), N-methyl PPIX, bile acids, and glutathione (GSH) in the liver. Metabolomic analysis also revealed bioactivation pathways of GSF that contributed to the formation of GSF-PPIX, GSF-GSH and GSF-proline adducts. GSF-PPIX is the precursor of N-methyl PPIX. A six-fold increase of N-methyl PPIX was observed in the liver of mice after GSF treatment. N-methyl PPIX strongly inhibits ferrochelatase, the enzyme that converts PPIX to heme, and leads to PPIX accumulation. Excessive PPIX in the liver results in bile duct blockage and disturbs bile acid homeostasis. The accumulation of GSH in the liver was likely due to Nrf2-mediated upregulation of GSH synthesis. In summary, this study provides the biochemical basis of GSF-induced liver injury that can be used to understand the pathophysiology of EPP-associated liver injury in humans.