Toxicology International (Formerly Indian Journal of Toxicology)

Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

Modulation of Adriamycin-Induced Hepatotoxicity and Genotoxicity by Selective Inhibition of Phosphodiesterase-5 with Sildenafil in Wistar Rats


Affiliations
1 Department of Biochemistry, Bowen University, Iwo, Osun State, Nigeria
2 Department of Veterinary Anatomy, University of Ibadan, Ibadan, Nigeria
3 Department of Pharmacology, School of Medical Sciences, University of Cape Coast, Cape Coast, Ghana
     

   Subscribe/Renew Journal


This study investigated the effect of selective inhibition of phosphodiesterase-5 on hepatotoxicity and genotoxicity induced by adriamycin in rats. Thirty male Wistar rats (150 - 250 g) were randomly assigned into six groups of 5 rats/group. Negative, positive and sildenafil controls received physiological saline (10 ml/kg, p.o.), adriamycin (20 mg/kg, i.p.) and sildenafil (20 mg/kg, p.o.) respectively. Three separate groups were pretreated with sildenafil (5, 10 and 20 mg/kg respectively) prior to adriamycin injection. Adriamycin increased activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP). This was associated with degeneration and severe central venous congestion in hepatic cells and marked micronuclei formation in erythrocytes. Sildenafil (5 mg/kg) reduced AST and ALP activities by 18.7 % (p<0.001) and 14.1 % (p<0.01) respectively in the adriamycin-treated rats without any significant change in ALT and GGT activities even at 10 mg/kg. Although, sildenafil (20 mg/kg) raised GGT activity by 77.4% and 51.6% in normal and adriamycin-treated rats respectively, these effects were not significant when compared with control. Similarly, total protein and albumin did not change significantly across the various treatment groups. However, sildenafil significantly (p<0.05) increased glutathione levels at all doses and significantly reduced micronuclei formation by 65.5% and ameliorated morphological damage associated with adriamycin toxicity. Our data suggest that low doses of the phosphodiesterase-5 inhibitor, sildenafil, may protect against adriamycin-induced hepatotoxicity and genotoxicity.

Keywords

Hepatotoxicity, Genotoxicity, Adriamycin, Phosphodiesterase-5, Sildenafil.
User
Subscription Login to verify subscription
Notifications
Font Size

  • Priestman T. Cancer chemotherapy in clinical practice. Springer-Verlag London, UK press 2008.

  • Kolarovic J, Popovic M, Mikov M, Mitic R, Gvozdenovic LJ. Protective effects of celery juice in treatments with doxorubicin. Molecules 2009; 14: 1627-1638.

  • Kolarovic J, Popovic M, Zlinská J, Trivic S, Vojnovic M. Antioxidant activities of celery and parsley juices in rats treated with doxorubicin. Molecules 2010; 15: 6193-6204.

  • Ekor M, Odewabi AO, Kale OE, Bamidele TO, Adesanoye OA and Farombi EO. Modulation of paracetamol-induced hepatotoxicity by phosphodiesterase isozyme inhibition in rats: a preliminary study. J Basic Clin Physiol Pharmacol 2013, 24(1): 73 – 79.

  • Rodrigues BP, Campagnaro BP, Balarini CM, Pereira TMC, Meyrelles SS, Vasquez EC. Sildenafil ameliorates biomarkers of genotoxicity in an experimental model of spontaneous atherosclerosis. Lipids in Health and Disease 2013; 12:128

  • Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006; 43:S121– 31.

  • Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol 2007; 46:927 – 34.

  • Malyshev E, Tazi KA, Moreau R, Lebrec D. Discrepant effects of inducible nitric oxide synthase modulation on systemic and splanchnic endothelial nitric oxide synthase activity and expression in cirrhotic rats. J Gastroenterol Hepatol 2007; 22:2195– 201.

  • Sessa WC. eNOS at a glance. J Cell Sci 2004; 117:2427 – 9.

  • 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.

  • Matsumoto T, Kobayashi T, Kamata K. Phosphodiesterases in the vascular system. J Smooth Muscle Res 2003; 39:67 – 86.

  • Prisant LM. Phosphodiesterase-5 inhibitors and their hemodynamic effects. Curr Hypertens Rep 2006; 8:345 – 51.

  • Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the care and use of laboratory animals, 8th ed. Washington, DC: National Academy of Sciences, National Academies Press, 2011.

  • Reitman S, Frankel SA. Colorimetric method for the determination of serum glutamate-oxaloacetate and pyruvate transaminases. Am J Clin Pathol 1957; 28:56 – 63.

  • Belfield A, Goldberg D. Colorimetric determination of alkaline phosphatase activity. Enzyme 1971; 12: 561-566.

  • Szasz G. Clin. Chem 1969; 22: 124-136.

  • Gornall AG, Bardawill CJ, David MM. Determination of serum proteins by means of the Biuret reaction. J Biol Chem 1949; 177:751.

  • Doumas BT, Watson WA, Biggs HG. Albumin standards and the measurement of serum albumin with bromocresol green reaction. Clin Chem 1971; 22:616 – 22.

  • Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963; 61:882 – 8.

  • Varshney R, Kale RK. Effect of calmodulin antagonist on radiation induced lipid peroxidation in microsomes. Int J Radiat Biol 1990; 58:733 – 43.

  • 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 – 255.

  • Radfar M, Larijani B, Hadjibabaie M, Rajabipour B, Mojtahedi A and Abdollahi M. Effect of pentoxifylline on oxidative stress and levels of EGF and NO in blood of diabetic type-2 patients: A randomized, double-blind placebo-controlled clinical trial. Biomed Pharmacother 2005; 59: 302 – 306.

  • Abdollahi M, Bahreini-Moghadam A, Emani B, Fooladian F, Zafari K. Increasing intracellular cAMP and cGMP inhibits cadmium-induced oxidative stress in rat submandibular saliva. Comp Biochem Physiol C. Toxicol Pharmacol 2003; 135: 331 – 336.

  • Mohan M, Kamble S, Satyanarayana J, Nageshwar M, Redddy N. Protective effect of Solanum torvum on Doxorubicininduced hepatotoxicity in rats. Int J Drug Dev Res 2011; 3:131–8.

  • Davies NA, Hodges SJ, Pitsillides AA, Mookerjee RP, Jalan R, Mehdizadeh S. Hepatic guanylate cyclase activity is decreased in a model of cirrhosis: a quantitative cytochemistry study. FEBS Lett 2006; 580:2123 – 8.

  • Elrod JW, Greer JJM, Lefer DJ. “Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway,” American Journal of Physiology—Heart and Circulatory Physiology 2007; 292 (1): H342–H347.

  • Beckman JS, Koppenol WH. “Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly,” The American Journal of Physiology—Cell Physiology 1996; 271 (5) C1424–C1437.

  • Ebrahimi F, Shafaroodi H, Asadi S, Nezami BG, Ghasemi M, Rahimpour S, Rashemi M, Doostar Y, Dehpour AR. Sildenafil decreased cardiac cell apoptosis in diabetic mice: reduction of oxidative stress as a possible mechanism. Can J Physiol Pharmacol 2009; 87: 556-564.


Abstract Views: 510

PDF Views: 1




  • Modulation of Adriamycin-Induced Hepatotoxicity and Genotoxicity by Selective Inhibition of Phosphodiesterase-5 with Sildenafil in Wistar Rats

Abstract Views: 510  |  PDF Views: 1

Authors

Anne A. Adeyanju
Department of Biochemistry, Bowen University, Iwo, Osun State, Nigeria
Adedeji D. Ogunyemi
Department of Biochemistry, Bowen University, Iwo, Osun State, Nigeria
Oluwaseun Owolabi
Department of Biochemistry, Bowen University, Iwo, Osun State, Nigeria
Ololade Adesanya
Department of Biochemistry, Bowen University, Iwo, Osun State, Nigeria
Temilade Omideyi
Department of Biochemistry, Bowen University, Iwo, Osun State, Nigeria
Oluwasanmi O. Aina
Department of Veterinary Anatomy, University of Ibadan, Ibadan, Nigeria
Martins Ekor
Department of Pharmacology, School of Medical Sciences, University of Cape Coast, Cape Coast, Ghana

Abstract


This study investigated the effect of selective inhibition of phosphodiesterase-5 on hepatotoxicity and genotoxicity induced by adriamycin in rats. Thirty male Wistar rats (150 - 250 g) were randomly assigned into six groups of 5 rats/group. Negative, positive and sildenafil controls received physiological saline (10 ml/kg, p.o.), adriamycin (20 mg/kg, i.p.) and sildenafil (20 mg/kg, p.o.) respectively. Three separate groups were pretreated with sildenafil (5, 10 and 20 mg/kg respectively) prior to adriamycin injection. Adriamycin increased activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP). This was associated with degeneration and severe central venous congestion in hepatic cells and marked micronuclei formation in erythrocytes. Sildenafil (5 mg/kg) reduced AST and ALP activities by 18.7 % (p<0.001) and 14.1 % (p<0.01) respectively in the adriamycin-treated rats without any significant change in ALT and GGT activities even at 10 mg/kg. Although, sildenafil (20 mg/kg) raised GGT activity by 77.4% and 51.6% in normal and adriamycin-treated rats respectively, these effects were not significant when compared with control. Similarly, total protein and albumin did not change significantly across the various treatment groups. However, sildenafil significantly (p<0.05) increased glutathione levels at all doses and significantly reduced micronuclei formation by 65.5% and ameliorated morphological damage associated with adriamycin toxicity. Our data suggest that low doses of the phosphodiesterase-5 inhibitor, sildenafil, may protect against adriamycin-induced hepatotoxicity and genotoxicity.

Keywords


Hepatotoxicity, Genotoxicity, Adriamycin, Phosphodiesterase-5, Sildenafil.

References





DOI: https://doi.org/10.22506/ti%2F2016%2Fv23%2Fi2%2F146694