Allicin mitigates hepatic injury following cyclophosphamide administration via activation of Nrf2/ARE pathways and through inhibition of inflammatory and apoptotic machinery

Abstract

Treatment with anti-neoplastic agents, including cyclophosphamide (CP), is associated with several adverse reactions. Here, we distinguished the potential protective effect of allicin against CP-mediated hepatotoxicity in rats. To assess the effect of allicin, four experimental groups were used, with 7 rats per group, including control, allicin (10 mg/kg), CP (200 mg/kg), and allicin + CP-treated groups. All groups were treated for 10 days. Blood and liver samples were collected for biochemical, molecular, and histological analyses. Treatment with CP led to deformations in the liver tissue that were associated with higher liver function markers (alanine transaminase, aspartate transaminase, and alkaline phosphatase). Additionally, a disturbance in the redox balance was observed after CP exposure, as indicated by increased levels of oxidants, including malondialdehyde and nitric oxide, and the decreased levels of endogenous antioxidants, including glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase. At the molecular level, CP treatment resulted in reduced expression of the Nrf2/ARE pathway and other genes related to this pathway, including NAD(P)H quinone dehydrogenase 1 and glutamate-cysteine ligase catalytic subunit. CP also led to a hyper-inflammatory response in hepatic tissue, with increased production of pro-inflammatory cytokines, including tumor necrosis factor-alpha and interlukin-1beta, and upregulation of nitric oxide synthase 2. CP also enhanced the immunoreactivity of the profibrogenic cytokine, transforming growth factor-beta, in liver tissue. Upregulation of caspase 3 and Bcl-2-associated X protein and downregulation of B-cell lymphoma 2 were also observed in response to CP treatment. Treatment with allicin reversed the molecular, biochemical, and histological changes that occurred with CP exposure. These results suggest that allicin can be used in combination with CP to avoid hepatotoxicity.