A recent study has identified antihistamine chlorcyclizine (CCZ) as a potential therapeutic agent for treating liver damage caused by erythropoietic protoporphyria (EPP), a rare genetic disorder. The study, published in Cellular and Molecular Gastroenterology and Hepatology, explored the role of histamine signaling in protoporphyrin-IX (PP-IX) accumulation and its subsequent effects on liver function. This marks a significant step toward addressing the unmet need for treatments targeting liver complications in EPP patients.
Understanding Erythropoietic Protoporphyria (EPP)
EPP is a genetic disorder that results in a deficiency of ferrochelatase, an enzyme responsible for breaking down heme precursors. As a result, PP-IX builds up in the liver and erythroid precursors, leading to symptoms such as photosensitivity. Although treatments exist for skin symptoms, liver damage remains largely untreated, with 10-25% of patients developing liver dysfunction and 1-4% progressing to end-stage liver failure.
Study Overview
The study utilized a zebrafish model to screen for potential compounds that could reduce PP-IX accumulation in the liver. After injecting transgenic zebrafish larvae with δ-aminolevulinic acid (ALA) and deferoxamine (DFO), which induce PP-IX overproduction, the researchers used fluorescence imaging to monitor PP-IX levels in the liver. Chlorcyclizine (CCZ) emerged as a leading candidate, showing promise in reducing PP-IX buildup.
Subsequent validation in primary mouse hepatocytes and in two mouse models of EPP—the Fechm1Pas mutant and DDC-fed mice—further confirmed the efficacy of CCZ in reducing PP-IX accumulation and mitigating liver damage. The study focused on various mechanisms, including the activation of bile acid receptors and the expression of PP-IX clearance transporters.
Key Findings
The results revealed that CCZ significantly reduced PP-IX accumulation in several experimental models. In zebrafish, CCZ lowered hepatic PP-IX fluorescence and promoted its excretion into the surrounding medium. In mice, CCZ treatment resulted in a dose-dependent reduction of PP-IX in liver tissue and erythrocytes, particularly in female mice. Plasma markers of liver injury, such as alanine aminotransferase (ALT) and alkaline phosphatase (ALP), were also reduced.
Interestingly, the effects of CCZ were more pronounced in female mice, with males showing a less substantial response. This sex-specific difference may provide insights into how gender influences the response to treatments for EPP-related liver disease.
CCZ also demonstrated the ability to reduce oxidative stress and protein aggregation in liver cells, suggesting an improvement in cellular stress responses. Histamine was identified as a key factor in the accumulation of PP-IX, with both H1- and H2-receptor blockade reducing PP-IX levels. Additionally, CCZ treatment reduced mast cell infiltration and histamine levels in the liver, particularly in female mice.
Mechanistic Insights
Further analysis of the CCZ mechanism revealed that the drug activated nuclear translocation of constitutive androstane receptor (CAR) and farnesoid X receptor (FXR), which in turn enhanced the expression of bile acid transporters such as MRP4 and BSEP. This pathway likely facilitates PP-IX excretion through bile, providing a potential route for clearing the toxic buildup associated with EPP.
Conclusion
While afamelanotide (SCENESSE®) is the only FDA-approved treatment for the skin symptoms of EPP, no therapies currently address the liver-related complications. The study highlights the potential of CCZ, an H1-antihistamine, as an effective treatment option for EPP-related liver disease. By reducing PP-IX accumulation, alleviating oxidative stress, and activating bile excretion pathways, CCZ offers new hope for patients struggling with liver dysfunction due to this rare genetic condition.
These findings suggest that antihistamines like CCZ could play a pivotal role in treating EPP-related liver disease and warrant further investigation as safe and effective therapeutic agents.
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