Molehin Olorunfemi R, Adeyanju Anne A, Adefegha Stephen A, Aina Oluwasanmi O, Afolabi Blessing A, Olowoyeye Ayorinde O, Oyediran Jesutomi A, Oladiran Opeyemi R
Department of Biochemistry, Faculty of Science, Ekiti State University, Ado-Ekiti. P.M.B.5363, Ado-Ekiti, Nigeria, Phone: +234 803 462 1267, E-mail:
Department of Biological Sciences, McPherson University, Seriki Sotayo, Ajebo, Nigeria.
J Basic Clin Physiol Pharmacol. 2018 Jan 26;29(1):29-35. doi: 10.1515/jbcpp-2017-0011.
Elevation of phosphodiesterase-5 (PDE5) activity converts cyclic guanosine monophosphate (cGMP) to 5'-GMP, a mechanism that could be associated with drug-mediated hepatotoxicity. This study investigated whether selective inhibition of PDE5 by sildenafil could offer protection against hepatotoxicity induced by carbon tetrachloride (CCl4).
CCl4 (0.5 mL/kg) was administered intraperitoneally to induce hepatotoxicity. The control group received normal saline. Sildenafil (5 mg, 10 mg, and 20 mg/kg, p.o.) was administered to CCl4-treated rats.
CCl4 significantly increased the serum levels of gamma glutamyl transferase (γ-GT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) and reduced total protein (TP) (p<0.05). Pretreatment with sildenafil moderately reduced ALP, AST, and ALT activities with modest increase in TP level. CCl4-induced changes in the antioxidant status of the liver were significantly improved by sildenafil, especially at the lowest dose of 5 mg/kg by elevating the levels of reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST) and preventing lipid peroxidation (p<0.05). Sildenafil did not significantly alter the total cholesterol and triglyceride levels. However, high-density lipoprotein (HDL) level was significantly increased by sildenafil (p<0.05).
The results from this study suggest that sildenafil, when used at low doses, may be a useful pharmacological protective agent against CCl4-induced hepatotoxicity.
磷酸二酯酶5（PDE5）活性升高会将环磷酸鸟苷（cGMP）转化为5'-鸟苷单磷酸（5'-GMP），这一机制可能与药物介导的肝毒性有关。本研究调查了西地那非对磷酸二酯酶5的选择性抑制是否能预防四氯化碳（CCl4）诱导的肝毒性。
腹腔注射CCl4（0.5 mL/kg）以诱导肝毒性。对照组给予生理盐水。给接受CCl4处理的大鼠灌胃西地那非（5 mg、10 mg和20 mg/kg）。
CCl4显著提高了血清γ-谷氨酰转移酶（γ-GT）、碱性磷酸酶（ALP）、天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平，并降低了总蛋白（TP）水平（p<0.05）。西地那非预处理适度降低了ALP、AST和ALT活性，并使TP水平略有升高。西地那非显著改善了CCl4诱导的肝脏抗氧化状态变化，尤其是在最低剂量5 mg/kg时，通过提高还原型谷胱甘肽（GSH）、谷胱甘肽过氧化物酶（GPx）、过氧化氢酶（CAT）、超氧化物歧化酶（SOD）和谷胱甘肽-S-转移酶（GST）水平并防止脂质过氧化（p<0.05）。西地那非未显著改变总胆固醇和甘油三酯水平。然而，西地那非显著提高了高密度脂蛋白（HDL）水平（p<0.05）。
本研究结果表明，低剂量使用时，西地那非可能是一种有效的预防CCl4诱导肝毒性的药理保护剂。
