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The protective effect of 7-hydroxycoumarin against cisplatin-induced liver injury is mediated via attenuation of oxidative stress and inflammation and upregulation of Nrf2/HO-1 pathway

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Abstract

Cisplatin (CIS) is an effective chemotherapy against different solid cancers. However, the adverse effects, including hepatotoxicity, limit its clinical use. 7-hydroxycoumarin (7-HC) possesses antioxidant and hepatoprotective activities, but its protective effect against CIS hepatotoxicity has not been investigated. This study evaluated the effect of 7-HC on liver injury, oxidative stress (OS), and inflammation provoked by CIS. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 2 weeks followed by intraperitoneal injection of CIS (7 mg/kg) at day 15. CIS increased serum transaminases, alkaline phosphatase (ALP), and bilirubin and provoked tissue injury accompanied by elevated reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO). Liver nuclear factor (NF)-κB p65, inducible NO synthase (iNOS), pro-inflammatory cytokines, Bax, and caspase-3 were upregulated, and antioxidant defenses and Bcl-2 were decreased in CIS-treated rats, while 7-HC prevented liver injury and ameliorated OS, inflammatory and apoptosis markers. In addition, 7-HC enhanced nuclear factor erythroid 2–related factor 2 (Nrf2), and heme oxygenase (HO)-1 in CIS-administered rats and in silico studies revealed its binding affinity toward HO-1. In conclusion, 7-HC protected against CIS hepatotoxicity by mitigating OS and inflammatory response and modulating Nrf2/HO-1 pathway.

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Acknowledgements

Princess Nourah bint Abdulrahman University Researchers Supporting Project Number (PNURSP2023R381), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Funding

Princess Nourah bint Abdulrahman University Researchers Supporting Project Number (PNURSP2023R381), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

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Authors and Affiliations

  1. Physiology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, 62514, Egypt

    Demiana H. Sami & Ayman S. Soliman

  2. Physiology Department, Faculty of Medicine, Cairo University, Giza, 12613, Egypt

    Akef A. Khowailed

  3. Department of Biology, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, 11671, Saudi Arabia

    Reem S. Alruhaimi

  4. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University-Assiut Branch, Assiut, 71524, Egypt

    Emad H. M. Hassanein

  5. Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt

    Emadeldin M. Kamel

  6. Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt

    Ayman M. Mahmoud

  7. Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, M1 5GD, UK

    Ayman M. Mahmoud

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  1. Demiana H. Sami
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Contributions

Conceptualization: A.M.M., A.A.K., and A.S.S.; data curation: D.H.S., A.M.M., A.S.S., and E.M.K.; formal analysis: A.M.M.; investigation: D.H.S., A.M.M., A.S.S., E.M.K., and E.H.M.H.; methodology: D.H.S., A.M.M., A.S.S., E.M.K., and E.H.M.H.; project administration: R.S.A., A.M.M., and A.A.K.; resources: A.M.M., R.S.A., M.A.E., and E.M.K.; supervision: A.M.M.; validation: A.M.M.; visualization: A.M.M.; writing — original draft: D.H.S., A.S.S., A.M.M., and E.M.K.; writing — review and editing: A.M.M.

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Correspondence to Ayman M. Mahmoud.

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All animal experiments and procedures were approved by the Institutional Research Ethics Committee of Beni-Suef University (Ethical approval no.: 020–90).

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Sami, D.H., Soliman, A.S., Khowailed, A.A. et al. The protective effect of 7-hydroxycoumarin against cisplatin-induced liver injury is mediated via attenuation of oxidative stress and inflammation and upregulation of Nrf2/HO-1 pathway. Environ Sci Pollut Res 30, 80181–80191 (2023). https://doi.org/10.1007/s11356-023-27879-1

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