Sildenafil, a phosphodiesterase-5 inhibitor, offers protection against carbon tetrachloride-induced hepatotoxicity in rat
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Olorunfemi R. Molehin
,
Anne A. Adeyanju
Abstract
Background:
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).
Methods:
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.
Results:
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).
Conclusions:
The results from this study suggest that sildenafil, when used at low doses, may be a useful pharmacological protective agent against CCl4-induced hepatotoxicity.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared
Employment or leadership: None declared.
Honorarium: None declared.
Conflict of interest: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Subramoniam A, Pushpangadan P. Development of phytomedicine for liver diseases. Indian J Pharmacol 1999;31:166–75.Search in Google Scholar
2. Lee K, Yang Y, Wang Y. Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients. Hepatol Res 2008;38:1186–93.10.1111/j.1872-034X.2008.00388.xSearch in Google Scholar PubMed
3. Poli G, Albano E, Dianzani MU. The role of lipid peroxidation in liver damage. Chem Physiol Lipids 1987;45:117–42.10.1016/0009-3084(87)90063-6Search in Google Scholar
4. Recknagel RO, Glende EA, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther 1989;43:139–54.10.1016/0163-7258(89)90050-8Search in Google Scholar PubMed
5. Abraham P, Wilfred G, Cathrine S. Oxidative damage to the lipids and proteins of the lungs, testis and kidney of rats during carbon tetrachloride intoxication. Clin Chim Acta 1999;289:177–9.10.1016/S0009-8981(99)00140-0Search in Google Scholar PubMed
6. Nabeshima Y, Tazuma S, Kanno K, Hyogo H, Iwai M, Horiuchi M. Antifibrogenic function of angiotensin II type 2 receptor in CCl4-induced liver fibrosis. Biochem Biophys Res Commun 2006;346:658–64.10.1016/j.bbrc.2006.05.183Search in Google Scholar
7. Onori P, Morini S, Franchitto A, Sferra R, Alvaro D, Gaudio E. Hepatic microvascular features in experimental cirrhosis: a structural and morphometrical study in CCl4-treated rats. J Hepatol 2000;33:555–63.10.1016/S0168-8278(00)80007-0Search in Google Scholar PubMed
8. Brattin WJ, Glende Jr EA, Recknagel RO. Pathological mechanisms in carbon tetrachloride hepatotoxicity. J Free Radic Biol Med 1985;1:27–38.10.1016/0748-5514(85)90026-1Search in Google Scholar PubMed
9. Rajesh MG, Latha MS. Protective activity of Glycyrrhiza glabra Linn on carbon tetrachloride- induced peroxidative damage. Indian J Pharmacol 2004;36:284–87.Search in Google Scholar
10. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 2006;5:689–702.10.1038/nrd2030Search in Google Scholar PubMed PubMed Central
11. Moustafa YM, Khoder DM, El-awady EE, Zaitone SA. Sildenafil citrate protects against gastric mucosal damage induced by indomethacin in rats. Eur Rev Med Pharmacol Sci 2013;17: 179–88.Search in Google Scholar PubMed
12. Bernardes FP, Batista AT, Porto ML, Elisardo C, Vasquez EC, Campagnaro BP. Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells. Lipids Health Dis 2016;15:100.10.1186/s12944-016-0268-6Search in Google Scholar PubMed PubMed Central
13. Inan M, Uz YH, Kizilay G, Topcu-Tarladacalisir YB, Sapmaz-Metin M, Meryem, MA, et al. Protective effect of sildenafil on liver injury induced by intestinal ischemia/reperfusion. J Ped Surg 2013;48:1707–15.10.1016/j.jpedsurg.2012.12.054Search in Google Scholar PubMed
14. Taskin MI, Yah A, Ardali E, Bacioglu E, Inceboz U. Protective effects of sildenafil citrate administration on cisplatin-induced ovarian damage in rats. J Gynecol Endocrinol 2015;31:272–77.10.3109/09513590.2014.984679Search in Google Scholar
15. European Union; Directive 2010/63/EU of the European parliament and of the council of 22 September 2010 on the protection of animals used for scientific purposes. Official Journal of the European Union 2010 Oct 20 (No. L 276/33).Search in Google Scholar
16. Lawerence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat’s liver. Biochem Biophys Res Commun 1961;71:952–8.10.1016/0006-291X(76)90747-6Search in Google Scholar
17. Habig WH, Pabst MJ, Jacoby WB. Glutathione-S-transferases: the first enzymatic step in mercaptoric acid formation. J Biol Chem 1974;249:7130–9.10.1016/S0021-9258(19)42083-8Search in Google Scholar PubMed
18. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351–8.10.1016/0003-2697(79)90738-3Search in Google Scholar PubMed
19. Adam-Vizi V, Seregi M. Receptor dependent stimulatory effect of noradrenaline on Na+/K+ ATPase in rat brain homogenate: role of lipid peroxidation. Biochem Pharmacol 1982;31:2231–6.10.1016/0006-2952(82)90106-XSearch in Google Scholar
20. Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR. Bromobenzene induced liver necrosis: protective role of glutathione and evidence for 3,4 bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 1974;11:151–69.10.1159/000136485Search in Google Scholar PubMed
21. Misra HP, Fridovich I. The generation of superoxide radical during the antioxidant of hemoglobin. J Biol Chem 1972;247:6960–2.10.1016/S0021-9258(19)44679-6Search in Google Scholar PubMed
22. Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with Folin phenol reagent. J Biol Chem 1951;193:265–75.10.1016/S0021-9258(19)52451-6Search in Google Scholar PubMed
23. Asru KS. Colorimetric assay of catalase. Anal Biochem 1972;47:389–94.10.1016/0003-2697(72)90132-7Search in Google Scholar PubMed
24. Loureiro-Silva MR, Iwakiri Y, Abraldes J, Haq GO, Groszmann RJ. Increased phosphodiesterase-5expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers. J Hepatol 2006;44:886–93.10.1016/j.jhep.2006.01.032Search in Google Scholar PubMed
25. Blei AT. Portal hypertension and its complications. Curr Opin Gastroenterol 2007;23:275–82.10.1097/MOG.0b013e3280b0841fSearch in Google Scholar PubMed
26. DeLeve LD. Hepatic microvasculature in liver injury. Semin Liver Dis 2007;27:390–400.10.1055/s-2007-991515Search in Google Scholar PubMed
27. Sessa WC. eNOS at a glance. J Cell Sci 2004;117:2427–9.10.1242/jcs.01165Search in Google Scholar PubMed
28. Bellamy TC, Wood J, Garthwaite J. On the activation of soluble guanylyl cyclase by nitric oxide. Proc Natl Acad Sci USA 2002;99:507–10.10.1073/pnas.012368499Search in Google Scholar PubMed PubMed Central
29. Matsumoto T, Kobayashi T, Kamata K. Phosphodiesterases in the vascular system. J Smooth Muscle Res 2003;39:67–86.10.1540/jsmr.39.67Search in Google Scholar PubMed
30. Prisant LM. Phosphodiesterase-5 inhibitors and their hemodynamic effects. Curr Hypertens Rep 2006;8:345–51.10.1007/s11906-006-0075-ySearch in Google Scholar PubMed
31. Lee K, Yang Y, Wang Y, Hou M, Lee F, Lin H, et al. Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients. Hepatol Res 2008;38:1186–93.10.1111/j.1872-034X.2008.00388.xSearch in Google Scholar PubMed
32. Ekor M, Odewabi AO, Kale OE, Bamidele TO, Adesanoye OA, Farombi EO. Modulation of paracetamol-induced hepatotoxicity by phosphodiesterase isozyme inhibition in rats: a preliminary study. J Basic Clin Physiol Pharmacol 2013;24:73–9.10.1515/jbcpp-2012-0043Search in Google Scholar PubMed
33. Milani E, Nikfar S, Khorasani R, Zamani MJ, Abdollahi M. Reduction of diabetes-induced oxidative stress by phosphodiesterase inhibitors in rats. Comp Biochem Physiol 2005;140C:251–5.10.1016/j.cca.2005.02.010Search in Google Scholar PubMed
34. Balarini CM, Leal MA, Gomes IB, Pereira TM, Gava AL, Meyrelles SS, et al. Sildenafil restores endothelial function in the apolipoprotein E knockout mouse. J Transl Med 2013;11:3.10.1186/1479-5876-11-3Search in Google Scholar PubMed PubMed Central
35. Ghofrani HA, Pepke-Zaba J, Barbera JA, Channick R, Keogh AM, Gomez-Sanchez MA, et al. Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S68–72.10.1016/j.jacc.2004.02.031Search in Google Scholar PubMed
36. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. The Am J Physiol-Cell Physiol 1996;271:C1424–37.10.1152/ajpcell.1996.271.5.C1424Search in Google Scholar PubMed
37. Yildız H, Durmus AS, Simsek H, Yaman M. Dose-dependent protective effect of sildenafil citrate on testicular injury after torsion/detorsion in rats. Andrologia 2012;44:300–6.10.1111/j.1439-0272.2011.01181.xSearch in Google Scholar PubMed
38. Ebrahimi F, Shafaroodi H, Asadi S, Nezami BG, Ghasemi M, Rahimpour S, et al. Sildenafil decreased cardiac cell apoptosis in diabetic mice: reduction of oxidative stress as a possible mechanism. Can J Physiol Pharmacol 2009;87:556–64.10.1139/Y09-036Search in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Behavior and Neuroprotection
- Seizure vulnerability and anxiety responses following chronic co-administration and acute withdrawal of caffeine and ethanol in a rat model
- Cardiovascular Function
- Indexes of the erythropoietin level in the blood plasma of chronic heart failure patients with anemia
- Oxidative Stress
- Ameliorative effect of gallic acid on doxorubicin-induced cardiac dysfunction in rats
- Sildenafil, a phosphodiesterase-5 inhibitor, offers protection against carbon tetrachloride-induced hepatotoxicity in rat
- Metabolism
- Antidiabetic potential of polyphenolic-rich fraction of Tamarindus indica seed coat in alloxan-induced diabetic rats
- Effect of L-carnitine on diabetes-induced changes of skeletal muscles in rats
- Inflammation
- Swimming, but not vitamin E, ameliorates prothrombotic state and hypofibrinolysis in a rat model of nonalcoholic fatty liver disease
- Infection
- In vitro ovicidal activity of poly lactic acid curcumin-nisin co-entrapped nanoparticle against Fasciola spp. eggs and its reproductive toxicity
- Phytotherapy
- Assessment of the antioxidant, thrombolytic, analgesic, anti-inflammatory, antidepressant and anxiolytic activities of leaf extracts and fractions of Tetracera sarmentosa (L.) Vahl
- Anti-invasive and antiproliferative effects of Pleurotus ostreatus extract on acute leukemia cell lines
- Letter to the Editor
- Is antiarrhythmic drug effectiveness stable? Extrapolating ICD in different space weather conditions
- Acknowledgment
Articles in the same Issue
- Frontmatter
- Behavior and Neuroprotection
- Seizure vulnerability and anxiety responses following chronic co-administration and acute withdrawal of caffeine and ethanol in a rat model
- Cardiovascular Function
- Indexes of the erythropoietin level in the blood plasma of chronic heart failure patients with anemia
- Oxidative Stress
- Ameliorative effect of gallic acid on doxorubicin-induced cardiac dysfunction in rats
- Sildenafil, a phosphodiesterase-5 inhibitor, offers protection against carbon tetrachloride-induced hepatotoxicity in rat
- Metabolism
- Antidiabetic potential of polyphenolic-rich fraction of Tamarindus indica seed coat in alloxan-induced diabetic rats
- Effect of L-carnitine on diabetes-induced changes of skeletal muscles in rats
- Inflammation
- Swimming, but not vitamin E, ameliorates prothrombotic state and hypofibrinolysis in a rat model of nonalcoholic fatty liver disease
- Infection
- In vitro ovicidal activity of poly lactic acid curcumin-nisin co-entrapped nanoparticle against Fasciola spp. eggs and its reproductive toxicity
- Phytotherapy
- Assessment of the antioxidant, thrombolytic, analgesic, anti-inflammatory, antidepressant and anxiolytic activities of leaf extracts and fractions of Tetracera sarmentosa (L.) Vahl
- Anti-invasive and antiproliferative effects of Pleurotus ostreatus extract on acute leukemia cell lines
- Letter to the Editor
- Is antiarrhythmic drug effectiveness stable? Extrapolating ICD in different space weather conditions
- Acknowledgment
