The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic ProtoporphyriaSummary
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...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X25000049 |
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| author | Ning Kuo Pei Li Juliana Bragazzi Cunha Lu Chen Jordan A. Shavit M. Bishr Omary |
| author_facet | Ning Kuo Pei Li Juliana Bragazzi Cunha Lu Chen Jordan A. Shavit M. Bishr Omary |
| author_sort | Ning Kuo |
| collection | DOAJ |
| description | 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-aminolevulinic 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 (PMHs), 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 quantitative polymerase chain reaction. Results: Chlorcyclizine-treated zebrafish larvae, DDC-fed, and transgenic EPP mice manifested reduced hepatic PP-IX levels compared with controls. Histamine increased PP-IX accumulation in porphyrin-stressed hepatocytes, whereas H1/H2-receptor blockade decreased PP-IX levels. In both mouse models, chlorcyclizine lowered PP-IX levels 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 PMHs, 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 2 experimental EPP models. Chlorcyclizine and/or other antihistamines provide a potential therapeutic strategy to treat EPP-associated liver disease via decreasing PP-IX accumulation. |
| format | Article |
| id | doaj-art-c1b6d9e7d3fe4e978c3cb6f4bc6a39ae |
| institution | DOAJ |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-c1b6d9e7d3fe4e978c3cb6f4bc6a39ae2025-08-20T03:05:18ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-0119610146310.1016/j.jcmgh.2025.101463The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic ProtoporphyriaSummaryNing Kuo0Pei Li1Juliana Bragazzi Cunha2Lu Chen3Jordan A. Shavit4M. Bishr Omary5Robert Wood Johnson Medical School, and Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey; Current affiliation: Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CaliforniaRobert Wood Johnson Medical School, and Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New JerseyRobert Wood Johnson Medical School, and Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey; Current affiliation: Division of Hospital Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MichiganRobert Wood Johnson Medical School, and Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New JerseyDepartment of Pediatrics, Division of Pediatric Hematology/Oncology, University of Michigan, Ann Arbor, Michigan; Department of Human Genetics, University of Michigan, Ann Arbor, MichiganRobert Wood Johnson Medical School, and Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey; Correspondence Address correspondence to: Bishr Omary, MD, PhD, Center for Advanced Biotechnology and Medicine, Rutgers University. 679 Hoes Lane West, Piscataway, New Jersey.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-aminolevulinic 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 (PMHs), 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 quantitative polymerase chain reaction. Results: Chlorcyclizine-treated zebrafish larvae, DDC-fed, and transgenic EPP mice manifested reduced hepatic PP-IX levels compared with controls. Histamine increased PP-IX accumulation in porphyrin-stressed hepatocytes, whereas H1/H2-receptor blockade decreased PP-IX levels. In both mouse models, chlorcyclizine lowered PP-IX levels 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 PMHs, 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 2 experimental EPP models. Chlorcyclizine and/or other antihistamines provide a potential therapeutic strategy to treat EPP-associated liver disease via decreasing PP-IX accumulation.http://www.sciencedirect.com/science/article/pii/S2352345X25000049Anti-H1 Histamine BlockerAnti-H2 Histamine BlockerFerrochelatasePorphyria-related Liver Disease |
| spellingShingle | Ning Kuo Pei Li Juliana Bragazzi Cunha Lu Chen Jordan A. Shavit M. Bishr Omary The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic ProtoporphyriaSummary Cellular and Molecular Gastroenterology and Hepatology Anti-H1 Histamine Blocker Anti-H2 Histamine Blocker Ferrochelatase Porphyria-related Liver Disease |
| title | The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic ProtoporphyriaSummary |
| title_full | The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic ProtoporphyriaSummary |
| title_fullStr | The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic ProtoporphyriaSummary |
| title_full_unstemmed | The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic ProtoporphyriaSummary |
| title_short | The Histamine Pathway is a Target to Treat Hepatic Experimental Erythropoietic ProtoporphyriaSummary |
| title_sort | histamine pathway is a target to treat hepatic experimental erythropoietic protoporphyriasummary |
| topic | Anti-H1 Histamine Blocker Anti-H2 Histamine Blocker Ferrochelatase Porphyria-related Liver Disease |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X25000049 |
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