Hydroxychloroquine ameliorates dasatinib-induced liver injury via decrease in hepatic lymphocytes infiltration

Area of Science:

• Pharmacology
• Hepatology
• Immunology

Background:

• Dasatinib is a crucial treatment for chronic myeloid leukemia.
• Idiosyncratic hepatotoxicity is a reported adverse effect of dasatinib therapy.
• Understanding mechanisms of drug-induced liver injury is critical for patient safety.

Purpose of the Study:

• To investigate the chemopreventive potential of hydroxychloroquine against dasatinib-induced hepatotoxicity.
• To elucidate the role of immune cell infiltration in dasatinib-induced liver injury.
• To assess the impact of hydroxychloroquine on oxidative stress markers and liver enzymes.

Main Methods:

• Balb/c mice were administered dasatinib, hydroxychloroquine, or a combination.
• Liver injury was assessed via serum biomarkers (AST, ALT) and histopathology (H&E, Masson's trichrome, reticulin staining).
• Immune cell infiltration (CD3+, CD4+, CD8+, CD20+) and antioxidant enzyme gene expression (CAT, SOD-2, GPX-1) were quantified.

Main Results:

• Dasatinib significantly increased liver injury biomarkers and lymphocyte infiltration, alongside downregulating antioxidant enzyme gene expression.
• Hydroxychloroquine combined with dasatinib showed a slight increase in AST/ALT but significantly reduced lymphocyte infiltration compared to dasatinib alone.
• Dasatinib induced an immune response leading to hepatocyte destruction, while hydroxychloroquine ameliorated this by reducing T and B cell infiltration.

Conclusions:

• Dasatinib induces hepatotoxicity, partly mediated by an increase in hepatic immune cell infiltration.
• Hydroxychloroquine demonstrates chemopreventive effects against dasatinib-induced liver injury.
• Hydroxychloroquine may protect the liver by modulating the immune response and reducing inflammatory cell infiltration.