Abstract
High-calorie diet, alcohol, and multiple drug use increase reactive oxygen species (ROS) and cause liver damage. ROS are crucial in the initiation/progression of liver diseases. Antioxidants have beneficial effects but produce clinically complex results. The hydrogen sulfide (H2S) pathway is considered a promising therapeutic target since it plays role in the pathogenesis/treatment of liver diseases. Sildenafil exerts antioxidant and hepatoprotective effects by increasing specific antioxidants such as superoxide dismutase, glutathione peroxidase, and regulating the Keap1/Nrf2 pathway which are common mechanisms underlying the effects of H2S. We aimed to determine if H2S has a role in the hepatoprotective and antioxidant effects of sildenafil. The effect of sildenafil on endogenous H2S production was elucidated with an H2S microsensor in the presence/absence of pyrogallol-induced oxidative stress and H2S synthesis inhibitor aminoxyacetic acid (AOAA) in the liver. The relation between the antioxidant effect of sildenafil and H2S was determined by luminol and lucigenin chemiluminescence. Sildenafil increased L-cysteine-induced H2S synthesis in the healthy liver and prevented the pyrogallol-induced reduction in H2S production. Sildenafil decreased the ROS production induced by pyrogallol and its protective effect was inhibited by AOAA. These results reveal that H2S is a new pharmacological mechanism of action of sildenafil on the liver. Therefore, sildenafil can be a potential therapeutic agent in treating many liver diseases in which H2S bioavailability is impaired. Additionally, the hepatoprotective effect of sildenafil by increasing endogenous H2S synthesis advances our knowledge in terms of developing H2S-targeting molecules.
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Acknowledgements
The authors would like to thank to the Ege University Office of Scientific Research Projects (THD-2022-23603) and The Scientific and Technological Research Council of Turkey (TUBITAK) 2211-C program.
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This work was supported by the Ege University Office of Scientific Research Projects (THD-2022–23603).
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Elif Alan Albayrak: Investigation, Writing – original draft, Formal analysis. Ozan Mert: Investigation, Formal analysis. Gulcan Demir: Investigation. Gulnur Sevin: Conceptualization, Writing – review & editing, Methodology, Resources. All authors read and approved the manuscript, all data were generated in-house, and no paper mill was used.
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The study was approved by Ege University Local Ethics Committee of Animal Experiments (Approval reference number: 2021–091). The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines were used.
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Alan Albayrak, E., Mert, O., Demir, G. et al. A new insight into the hepatoprotective effect of sildenafil: The role of H2S. Naunyn-Schmiedeberg's Arch Pharmacol 396, 2977–2985 (2023). https://doi.org/10.1007/s00210-023-02500-x
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DOI: https://doi.org/10.1007/s00210-023-02500-x