A new insight into the hepatoprotective effect of sildenafil: The role of H2S

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2023-11, Vol.396 (11), p.2977-2985
• Main Authors: Alan Albayrak, Elif, Mert, Ozan, Demir, Gulcan, Sevin, Gulnur
• Format: Article
• Language: English
• Subjects: Antioxidants; Bioavailability; Biomedical and Life Sciences; Biomedicine; Chemiluminescence; Glutathione peroxidase; Hydrogen sulfide; Liver diseases; Neurosciences; Oxidative stress; Pharmacology/Toxicology; Pyrogallol; Reactive oxygen species; Sildenafil; Therapeutic targets
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-023-02500-x

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 (H 2 S) 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 H 2 S. We aimed to determine if H 2 S has a role in the hepatoprotective and antioxidant effects of sildenafil. The effect of sildenafil on endogenous H 2 S production was elucidated with an H 2 S microsensor in the presence/absence of pyrogallol-induced oxidative stress and H 2 S synthesis inhibitor aminoxyacetic acid (AOAA) in the liver. The relation between the antioxidant effect of sildenafil and H 2 S was determined by luminol and lucigenin chemiluminescence. Sildenafil increased L-cysteine-induced H 2 S synthesis in the healthy liver and prevented the pyrogallol-induced reduction in H 2 S production. Sildenafil decreased the ROS production induced by pyrogallol and its protective effect was inhibited by AOAA. These results reveal that H 2 S 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 H 2 S bioavailability is impaired. Additionally, the hepatoprotective effect of sildenafil by increasing endogenous H 2 S synthesis advances our knowledge in terms of developing H 2 S-targeting molecules.