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

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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.

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Authors and Affiliations

  1. Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

    Dongsheng Sun, Chen Sun, Gongcai Qiu & Lei Yao

  2. Department of General Surgery, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, Shandong, China

    Jian Yu

  3. Basic Medical Science, Histopathology Department, National Organization for Drug Control and Research, Giza, Egypt

    Hassan Al Sberi

  4. Department of Biology, Faculty of Science, Taif University, Taif, Saudi Arabia

    Hassan Al Sberi

  5. Chemistry Department, Faculty of Science, Helwan University, Helwan, 11795, Egypt

    Manar S. Fouda

  6. Basic Sciences Department, Preparatory Year, University of Ha’il, Hail, Saudi Arabia

    Mohamed S. Othman

  7. Chemistry Department, Faculty of Biotechnology, October University for Modern Science and Arts (MSA), Giza, Egypt

    Mohamed S. Othman

  8. Biology Department, College of Science and Humanities, Prince Sattam Bin Abdul Aziz University, Alkharj, Saudi Arabia

    Maha S Lokman

  9. Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt

    Maha S Lokman, Rami B. Kassab & Ahmed E. Abdel Moneim

  10. Biology Department, Faculty of Science and Arts, Al Baha University, Almakhwah Branch, Al Baha, Saudi Arabia

    Rami B. Kassab

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  1. Dongsheng Sun
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Contributions

Hassan Al Sberi, Maha S Lokman, and Rami B. Kassab: animal treatments, biochemical methodology, and histological and immunohistochemistry examinations. Manar S. Fouda and Mohamed S. Othman: molecular analysis. Dongsheng Sun and Chen Sun: resources, visualization, investigation, and software. Gongcai Qiu and Lei Yao: writing—reviewing and editing. Jian Yu and Ahmed E. Abdel Moneim: conceptualization, validation, and supervision.

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Correspondence to Jian Yu.

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The current experimental design was approved by the research ethical committee of the Helwan University (approval no. HU2019/Z/RK0420-09) in accordance with the National Institutes of Health (NIH) Guidelines for the Care and Use of Laboratory Animals, 8th edition (NIH Publication no. 85–23, revised 1985).

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Sun, D., Sun, C., Qiu, G. et al. Allicin mitigates hepatic injury following cyclophosphamide administration via activation of Nrf2/ARE pathways and through inhibition of inflammatory and apoptotic machinery. Environ Sci Pollut Res 28, 39625–39636 (2021). https://doi.org/10.1007/s11356-021-13392-w

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