Abstract
Adriamycin (ADR) is an anticancer drug that has a wide report of toxicity in various organs including testes and liver. This has brought limitation to its use in chemotherapy. Protocatechuic acid (PCA) is a phenolic acid present in several foods of plant origins. The aim of this study is to assess the possible action of PCA in ADR-induced reproductive and hepatic toxicities in rats. Thirty adult male rats of about 160–180 g in weight were separated into five groups: group 1 was given normal saline and served as control group, group 2 was administered 20 mg/kg of ADR intraperitoneally, groups 3 and 4 were administered ADR and separate doses of PCA (10 and 20 mg/kg body weight) respectively, while the group 5 rats received only 20 mg/kg of PCA. Pre-treatment with PCA significantly improved sperm motility, sperm count, and viability in ADR-induced rats. Furthermore, elevated levels of testes and liver malondialdehyde were significantly reduced in rats treated with PCA. Also, the increased serum alkaline phosphatase, aspartate transaminase, total cholesterol, triglyceride total protein, and albumin levels in ADR-induced rats were brought near the control value by PCA treatment. Conversely, reduction in the levels of testes and liver glutathione as well as the serum high-density lipoprotein (HDL) cholesterol level in ADR group was significantly raised in PCA-treated rats. Therefore, PCA may represent a natural and promising compound for mitigating against oxidative stress-mediated toxicities.
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Abd El-Aziz MA, Othman AI, Amer M, ElMissiry MA (2001) Potential protective role of angiotensin-converting enzyme inhibitors captopril and enalapril against adriamycin-induced acute cardiac and hepatic toxicity in rats. J Appl Toxicol 21:469–473
Adam-Vizi V, Seregi M (1982) Receptor dependent stimulatory effect of noradrenaline on Na+/K+ ATPase in rat brain homogenate: role of lipid peroxidation. Biochem Pharmacol 31:2231–2236
Adefegha AS, Omojokun OS, Oboh G (2015) Modulatory effect of protocatechuic acid on cadmium induced nephrotoxicity and hepatoxicity in rats in vivo. Springer Plus 4:619. https://doi.org/10.1186/s40064-015-1408-6
Adefegha AS, Oboh G, Omojokun OS, Adefegha OM (2016) Alterations of Na + /K + -ATPase, cholinergic and antioxidant enzymes activity by protocatechuic acid in cadmium-induced neurotoxicity and oxidative stress in Wistar rats. Biomed Pharmacother 83:559-568
Akomolafe SF, Oboh G, Akindahunsi AA, Afolayan AJ (2017) Ethanol-induced male infertility: effects of aqueous leaf extract of Tetracarpidium conophorum. Andrologia 49. https://doi.org/10.1111/and.12759
Asru KS (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394
Betty RK, Jonathan AC (2003) Essential medical statistics 2nd edition. Blackwell science, Oxford, pp 15–409
Cui JX, Li CL, Guo WM (2007) Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy. J Control Release 118:204–215
Disbrey BD, Rack JH (1970) Book of histological laboratory methods. Harcourt Brace/ChurchillLivingstone, London
Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51:691–743
Dudka J, Gieroba R, Korga A, Burdan F, Matysiak W, Jodlowska-Jedrych B, Mandziuk S, Korobowicz E, Murias M (2012) Different effects of resveratrol on dose-related doxorubicin-induced heart and liver toxicity. Evid-Based Compl Alternat Med 2012:1–10. https://doi.org/10.1155/2012/606183
Farombi OE, Adedara IA, Awoyemi O, Njoku C, Micah G, Esogwa C, Owumi SE, Olopade J (2015) Dietary protocatechuic acid ameliorates dextran sulphate sodium-induced ulcerative colitisand hepatotoxicity in rats. Food Funct 7:913–921. https://doi.org/10.1039/C5FO01228G
Gillick J, Giles S, Bannigan J, Puri P (2002) Cell death in the early adriamycin rat model. Pediatr Surg Int 18:576–580
Grigorian A, O’Brien CB (2014) Hepatotoxicity secondary to chemotherapy. J Clin Transl Hepatol 2(2):95–102
Harini R, Pugalendi KV (2010) Antioxidant and antihyperlipidaemic activity of protocatechuic acid on streptozotocin diabetic rats. Red Rep 15:71–80
Hou M, Chrysis D, Nurmio M, Parvinen M, Eksborg S, Söder O, Jahnukainen K (2005) Doxorubicin induces apoptosis in germ line stem cells in the immature rat testis and amifostine cannot protect against this cytotoxicity. Cancer Res 65:9999–10005
Howell SJ, Shalet SM (2005) Spermatogenesis after cancer treatment: damage and recover. J Natl Cancer Inst Monogr 34:12–17
Injac R, Strukelj B (2008) Recent advances in protection against doxorubicin-induced toxicity. Tech Cancer Res Treat 7(6):497–516
Injac R, Boskovic M, Perse M, Koprivec-Furlan E, Cerar A, Djordjevic A, Strukelj B (2008) Acute doxorubicin nephrotoxicity in rats with malignant neoplasm can be successfully treated with fullerenol C60(OH)24 via suppression of oxidative stress. Pharmacol Rep 60:742–749
Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR (1974) Bromobenzene induced liver necrosis: protective role of glutathione and evidence for 3,4 bromobenzene oxide as the hepatotoxic metabolite. Pharmacol 11:151–169
Kakkar S, Bais S (2014) A review on protocatechuic acid and its pharmacological potential. ISRN Pharmacol 2014:1–9
Kalender S, Kavutcu M, Kalender Y, Olcay E, Yel M, Ates A (2001) Protective role of antioxidant vitamin E and catechin on doxorubicin-induced cardiotoxicity in rats. Cancer Res Ther Cont 11:175–182
Lawerence RA, Burk RF (1961) Glutathione peroxidase activity in selenium-deficient rat’s liver. Biochem Biophys Res Commun 71:952–958
Lende AB, Kshirsagar AD, Deshpande AD, Muley MM, Patil RR, Bafna PA, Naik SR (2011) Anti-inflammatory and analgesic activity of protocatechuic acid in rats and mice. Inflammopharmacol 19:255–263
Liu WH, Lin CC, Wang ZH, Mong MC, Yin MC (2010) Effects of protocatechuic acid on trans fat induced hepatic steatosis in mice. J Agric Food Chem 58:10247–10252
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275
Lui RC, Laregina MC, Herbold DR, Johnson FE (1986) Testicular cytotoxicity of intravenous doxorubicin in rats. J Urol 136:940–943
Masella R, Cantafora A, Modesti D, Cardilli A, Gennaro L, Bocca A, Coni E (1999) Antioxidant activity of 3,4-DHPEA-EA and protocatecuic acid: a comparative assessment with other olive oil biophenols. Redox Rep 4:113–121
Masella R, Santangelo CD, Archivio M, Li Volti G, Giovannini C, Galvano F (2012) Protocatechuic acid and human disease prevention: biological activities and molecular mechanisms. Curr Med Chem 19:2901–2917
McNulty TJ, Taylor CW (1999) Extracellular heavy metal ions stimulate Ca2+ mobilization in hepatocytes. J Biochem 339:555–561
Mishra MD, Bhiwgade DA (2007) Doxorubicin mediated oxidative stress induced degeneration of testicular tissues causes male sterility in rats. J Cell Tissue Res 7(1):861–866
Misra HP, Fridovich I (1972) The generation of superoxide radical during the antioxidant of hemoglobin. J Biol Chem 247:6960–6962
Mohamed RH, Karam RA, Amer MG (2011) Epicatechin attenuates doxorubicin-induced brain toxicity: critical role of TNF-α, iNOS and NF-κB. Brain Res Bull 86(1):22–28
Mohan I, Kumar K, Naidu M, Khan M, Sundaram C (2006) Protective effect of Cordipro against doxorubicin-induced cardiotoxicity in mice. Phytomed 13(4):222–229
Noakes DE, Parkinson TJ, England GCW (2001) Fertility and infertility in male animals, Arthurs Veterinary Reproduction and Obstetrics. Harcourt (Indian) private, limited 8th edn. pp 747
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Pant N, Srivastava SP (2003) Testicular and spermatotoxic effect of quinaphos in rats. J Appl Toxicol 23:271–274
Patel N, Joseph C, Corcoran GB, Ray SD (2010) Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p 53 expression while preventing apoptotic and necrotic cell death in the liver. Toxicol Appl Pharmacol 245(2):143–152
Sehgal R, Pandey AH (1984) Effect of cadmium chloride on testicular activities in guppy Lebistes reticulates. Comp Physiol Ecol 9:225–230
Shalizar A, Jalali S, Hasanzadeh S (2013) Crataegus monogyna fruit aqueous extract as a protective agent against doxorubicin-induced reproductive toxicity in male rats. Avicenna J Phytomed 3(2):159–170
Tacar O, Sriamornsak P, Dass CR (2013) Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol 65:157–170
Tanigaki R, Sueoka K, Tajima H, Nakabayashi A, Sato K, Asada H, Kato S, Hosoi Y, Yoshimura Y (2013) C-kit expression in spermatogonia damaged by doxorubicin exposure in mice. J Obstet Gynaecol Res 39:692–700
Ueda J, Saito N, Shimazu Y, Ozawa T (1996) A comparison of scavenging abilities of antioxidants against hydroxyl radicals. Arch Biochem Biophys 333:77–84
Vitaglione P, Donnarumma G, Napolitano A, Galvano F, Gallo A, Scalfi L (2007) Protocatechuic acid is the major human metabolite of cyaniding glucosides. J Nutr 137(9):2043–2048
Walaa HG, Howida S, Seif A, Amin S (2014) Protective effects of ruitn and/or hesperidin against doxorubicin-induced hepatotoxicity. Int J Clin Nutr 21:11–17
Wilhelm M, Jaeger DE, Schall-Cablitz H, Hafner D, Idel H (1996) Hepatic clearance and retention of aluminum: studies in the isolated perfused rat liver. Toxicol Lett 89(3):257–263
Yagmurcaa M, Orhan B, Hakan M, Onder S, Ahmet N, Ozcan K, Ahmet S (2007) Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res 38(4):380–385
Yang CC, Chen YT, Chen CH, Chiang JY, Zhen YY, Yip HK (2017) Assessment of doxorubicin-induced mouse testicular damage by the novel second-harmonic generation microscopy. Am J Translational Res 9(12):5275–5288
Yeh YC, Lai HC, Ting CT, Lee WL, Wang LC, Wang KY, Lai HCLTJ (2007) Protection by doxycycline against doxorubicin-induced oxidative stress and apoptosis in mouse testes. Biochem Pharmacol 74(7):969–980
Yeh Y, Liu T, Wang L, Lee H, Ting C, Lee W (2009) A standardized extract of Ginkgo biloba suppresses doxorubicin-induced oxidative stress and P53-mediated mitochondrial apoptosis in rats’ testes. British J Pharmacol 156(1):48–61
Yilmaz S, Atessahin A, Sahna E, Karahan I, Ozer S (2006) Protective effect of lycopene on adriamycin-induced nephrotoxicity. Toxicol 218:164–171
Yoshida S, Hiyoshi K, Ichinose T, Takano H, Oshio S, Sugawara I, Takeda K, Shibamoto T (2009) Effect of nanoparticles on the male reproductive system of mice. Int J Androl 32:337–342
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Molehin, O.R., Adeyanju, A.A., Adefegha, S.A. et al. Protocatechuic acid mitigates adriamycin-induced reproductive toxicities and hepatocellular damage in rats. Comp Clin Pathol 27, 1681–1689 (2018). https://doi.org/10.1007/s00580-018-2794-2
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DOI: https://doi.org/10.1007/s00580-018-2794-2