PUBLICATION
The histamine pathway is a target to treat hepatic experimental erythropoietic protoporphyria
- Authors
- Kuo, N., Li, P., Cunha, J.B., Chen, L., Shavit, J.A., Omary, M.B.
- ID
- ZDB-PUB-250119-4
- Date
- 2025
- Source
- Cellular and molecular gastroenterology and hepatology : 101463101463 (Journal)
- Registered Authors
- Shavit, Jordan
- Keywords
- anti-H1 histamine, anti-H2 histamine, ferrochelatase, porphyria-related liver disease
- MeSH Terms
-
- Protoporphyrins/metabolism
- Zebrafish
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Hepatocytes/drug effects
- Hepatocytes/metabolism
- Animals
- Deferoxamine/pharmacology
- Mice, Transgenic
- Disease Models, Animal
- Histamine H1 Antagonists/pharmacology
- Histamine H1 Antagonists/therapeutic use
- Mice
- Histamine*/metabolism
- Ferrochelatase/genetics
- Ferrochelatase/metabolism
- Male
- Protoporphyria, Erythropoietic*/drug therapy
- Protoporphyria, Erythropoietic*/metabolism
- Protoporphyria, Erythropoietic*/pathology
- PubMed
- 39824305 Full text @ Cell Mol Gastroenterol Hepatol
Citation
Kuo, N., Li, P., Cunha, J.B., Chen, L., Shavit, J.A., Omary, M.B. (2025) The histamine pathway is a target to treat hepatic experimental erythropoietic protoporphyria. Cellular and molecular gastroenterology and hepatology. :101463101463.
Abstract
Background & aims Erythropoietic protoporphyria (EPP) is caused by mutations in ferrochelatase which inserts iron into protoporphyrin-IX (PP-IX) to generate heme. EPP is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. Despite available drugs that address photosensitivity, treatment of EPP-related liver disease remains an unmet need.
Methods We administered delta-aminolaevulinic acid (ALA) and deferoxamine (DFO), which results in PP-IX overproduction and accumulation. High-throughput compound screening of ALA+DFO-treated zebrafish identified chlorcyclizine (first generation H1-antihistamine receptor blocker), as a drug that reduces zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes (PMH), transgenic Fechm1Pas EPP mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and qPCR.
Results Chlorcyclizine-treated zebrafish larvae, DDC-fed and transgenic EPP mice manifested reduced hepatic PP-IX levels compared to controls. Histamine increased PP-IX accumulation in porphyrin-stressed hepatocytes, while H1/H2-receptor blockade decreased PP-IX levels. In both mouse models, chlorcyclizine lowered PP-IX level in female but not male mice in liver, erythrocytes, and bone marrow; improved liver injury; decreased porphyrin-triggered protein aggregation and oxidation; and increased clearance of stool PP-IX. In PMH, chlorcyclizine induced nuclear translocation of constitutive androstane and farnesoid X receptors, and transactivated bile acid transporter expression. Knockdown of the transporters BSEP and MRP4 led to increased detection of sequestosome-1 (p62 protein) high-molecular-weight species. Chlorcyclizine also reduced hepatic mast cell number and histamine level in EPP mice.
Conclusions Histamine plays an important role in PP-IX accumulation in zebrafish and two experimental EPP models. Chlorcyclizine and/or other antihistamines, provide a potential therapeutic strategy to treat EPP-associated liver disease via decreasing PP-IX accumulation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping