Protective Effects of Xanthine Derivatives Against Arsenic Trioxide-Induced Oxidative Stress in Mouse Hepatic and Renal Tissues

Abstract

In this study, the protective efficacy of pentoxifylline (PTX) as a xanthine derivative against arsenic trioxide (ATO)-induced kidney and liver damage in mice was investigated. Thirty-six mice were divided into six groups, receiving intraperitoneal injections of saline, ATO, PTX, or a combination for four weeks. Blood samples were analyzed for serum biochemistry, while hepatic tissue underwent examination for histopathological changes and assessment of oxidative stress markers and antioxidant gene expression through Real-Time PCR. ATO exposure significantly increased serum markers (creatinine, ALT, BUN, ALP, AST) and induced histopathological changes in the liver. Moreover, it elevated renal and hepatic nitric oxide (NO) and lipid peroxidation (LPO) levels, and reduced antioxidant enzyme expression (CAT, GSR, GPx, MPO, SOD), total thiol groups (TTGs), and total antioxidant capacity (TAC). Conversely, PTX treatment effectively lowered serum hepatic and renal markers, improved antioxidant markers, and induced histopathological alterations. Notably, PTX did not significantly affect renal and hepatic NO levels. These findings suggest that PTX offers therapeutic potential in mitigating liver and acute kidney injuries induced by various insults, including exposure to ATO.

Keywords

arsenic trioxide (ATO) - kidney - liver - oxidative damage - pentoxifylline (PTX)

Publication History

Received: 23 November 2023

Accepted: 15 January 2024

Article published online:
13 February 2024

• References

• 1 Hu H, Chen E, Li Y. et al. Effects of arsenic trioxide on INF-gamma gene expression in MRL/lpr mice and human lupus. Biological trace element research 2018; 184: 391-397
• 2 Hughes MF. Arsenic toxicity and potential mechanisms of action. Toxicology letters 2002; 133: 1-16
• 3 Antman KH. Introduction: the history of arsenic trioxide in cancer therapy. The oncologist 2001; 6: 1-2
• 4 Saxena PN, Anand S, Saxena N. et al. Effect of arsenic trioxide on renal functions and its modulation by Curcuma aromatica leaf extract in albino rat. Journal of environmental biology 2009; 30 527–531
• 5 Samlaska CP, Winfield EA. Pentoxifylline. Journal of the American Academy of Dermatology 1994; 30: 603-621
• 6 Mandell G, Novick W. Pentoxifylline and leukocyte function: foreword and overview. Pentoxifylline and leukocyte function. Somerville, NJ: Hoechst-Roussel Pharmaceuticals; 1988
• 7 Hakim J, Mandell G, Movick W. Pentoxifylline and analogues: effects on leukocyte function. Karger; Basel: 1990
• 8 Ward A, Clissold SP. Pentoxifylline. Drugs 1987; 34: 50-97
• 9 Abdollahi M, Simaiee B. Stimulation by theophylline and sildenafil of rat submandibular secretion of protein, epidermal growth factor and flow rate. Pharmacological research 2003; 48: 445-449
• 10 Samardzic T, Stosic-Grujicic S, Maksimovic D. et al. Differential regulation of nitric oxide production by increase of intracellular cAMP in murine primary fibroblasts and L929 fibrosarcoma cell line. Immunology Letters 2000; 71: 149-155
• 11 Savaş Ç, Aras T, Çakmak M. et al. Pentoxifylline inhibits overflow and reduces intestinal reperfusion injury. Journal of pediatric surgery 1997; 32: 905-910
• 12 Hammerman C, Goldschmidt D, Caplan MS. et al. Amelioration of ischemia-reperfusion injury in rat intestine by pentoxifylline-mediated inhibition of xanthine oxidase. Journal of pediatric gastroenterology and nutrition 1999; 29: 69-74
• 13 Gheitasi I, Azizi A, Omidifar N. et al. Renoprotective effects of Origanum majorana methanolic L and carvacrol on ischemia/reperfusion-induced kidney injury in male rats. Evidence-Based Complementary and Alternative Medicine 2020;
• 14 Ansari S, Azarmehr N, Barmoudeh Z. et al. Evaluation of the protective potential of hydroalcoholic extract of Thymus daenensis on acetaminophen-induced nephrotoxicity in rats. Heliyon 2020; 6: e03898
• 15 Nili-Ahmadabadi A, Alibolandi P, Ranjbar A. et al. Thymoquinone attenuates hepatotoxicity and oxidative damage caused by diazinon: an in vivo study. Res Pharm Sci 2018; 13: 500-508
• 16 Sadeghi A, Bastin AR, Ghahremani H. et al. The effects of rosmarinic acid on oxidative stress parameters and inflammatory cytokines in lipopolysaccharide-induced peripheral blood mononuclear cells. Molecular Biology Reports 2020; 47: 3557-3566
• 17 Bastin AR, Sadeghi A, Abolhassani M. et al. Malvidin prevents lipopolysaccharide-induced oxidative stress and inflammation in human peripheral blood mononuclear cells. Iubmb Life 2020; 72: 1504-1514
• 18 Doustimotlagh AH, Taheri S, Mansourian M. et al. Extraction and identification of two flavonoids in phlomoides hyoscyamoides as an endemic plant of iran: the role of quercetin in the activation of the glutathione peroxidase, the improvement of the hydroxyproline and protein oxidation in bile duct-ligated rats. Current computer-aided drug design 2020; 16: 629-640
• 19 Doustimotlagh AH, Kokhdan EP, Vakilpour H. et al. Protective effect of Nasturtium officinale R. Br and quercetin against cyclophosphamide-induced hepatotoxicity in rats. Molecular biology reports 2020; 47: 5001-5012
• 20 Alorabi M, Cavalu S, Al-Kuraishy HM. et al. Pentoxifylline and berberine mitigate diclofenac-induced acute nephrotoxicity in male rats via modulation of inflammation and oxidative stress. Biomedicine & Pharmacotherapy 2022; 152: 113225
• 21 Salam O, Baiuomy AR, El-Shenawy SM. et al. Effect of pentoxifylline on hepatic injury caused in the rat by the administration of carbon tetrachloride or acetaminophen. Pharmacol Rep 2005; 57: 596-603
• 22 Parker R, Armstrong M, Corbett C. et al. Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis. Alimentary pharmacology & therapeutics 2013; 37: 845-854
• 23 Das N, Paul S, Chatterjee D. et al. Arsenic exposure through drinking water increases the risk of liver and cardiovascular diseases in the population of West Bengal, India. BMC public health 2012; 12: 1-9
• 24 Barai M, Ahsan N, Paul N. et al. Amelioration of arsenic-induced toxic effects in mice by dietary supplementation of Syzygium cumini leaf extract. Nagoya journal of medical science 2017; 79: 167-177
• 25 Kulshrestha A, Jarouliya U, Prasad G. et al. Arsenic-induced abnormalities in glucose metabolism: Bio- chemical basis and potential therapeutic and nutritional interventions. World Journal of Translational Medicine 2014; 3: 96-111
• 26 Brazy P, Balaban R, Gullans S. et al. Inhibition of Renal Metabolism. Relative effects of arsenate on sodium, phosphate, and glucose transport by the rabbit proximal tubule. The Journal of Clinical Investigation 1980; 66: 1211-1221
• 27 Bergquist ER, Fischer RJ, Sugden KD. et al. Inhibition by methylated organoarsenicals of the respiratory 2-oxo-acid dehydrogenases. Journal of organometallic chemistry 2009; 694: 973-980
• 28 Schwerdtle T, Walter I, Mackiw I. et al. Induction of oxidative DNA damage by arsenite and its trivalent and pentavalent methylated metabolites in cultured human cells and isolated DNA. Carcinogenesis 2003; 24: 967-974
• 29 Delnomdedieu M, Basti MM, Otvos JD. et al. Reduction and binding of arsenate and dimethylarsinate by glutathione: a magnetic resonance study. Chemico-biological interactions 1994; 90: 139-155
• 30 Verma R, Vasu A, Saiyed AA. Arsenic toxicity in mice and its possible amelioration. Journal of Environmental Sciences 2004; 16: 447-453
• 31 Mershiba SD, Dassprakash MV, Saraswathy SD. Protective effect of naringenin on hepatic and renal dysfunction and oxidative stress in arsenic intoxicated rats. Molecular biology reports 2013; 40: 3681-3691
• 32 Zhang Z, Gao L, Cheng Y. et al. Resveratrol, a natural antioxidant, has a protective effect on liver injury induced by inorganic arsenic exposure. BioMed Research International 2014; 2014: 1-7
• 33 Luo M, Dong L, Li J. et al. Protective effects of pentoxifylline on acute liver injury induced by thioacetamide in rats. International journal of clinical and experimental pathology 2015; 8: 8990-8996
• 34 Armagan I, Bayram D, Candan IA. et al. Effects of pentoxifylline and alpha lipoic acid on methotrexate-induced damage in liver and kidney of rats. Environmental toxicology and pharmacology 2015; 39: 1122-1131
• 35 Movassaghi S, Sharifi ZN, Mohammadzadeh F. et al. Pentoxifylline protects the rat liver against fibrosis and apoptosis induced by acute administration of 3, 4-methylenedioxymethamphetamine (MDMA or ecstasy). Iranian journal of basic medical sciences 2013; 16: 922-927
• 36 Manna P, Sinha M, Sil PC. Arsenic-induced oxidative myocardial injury: protective role of arjunolic acid. Archives of toxicology 2008; 82: 137-149
• 37 Sun T-L, Liu Z, Qi Z-J. et al. (-)-Epigallocatechin-3-gallate (EGCG) attenuates arsenic-induced cardiotoxicity in rats. Food and Chemical Toxicology 2016; 93: 102-110
• 38 Wei Z, Sun X, He Q. et al. Nephroprotective effect of magnesium isoglycyrrhizinate against arsenic trioxide‑induced acute kidney damage in mice. Experimental and Therapeutic Medicine 2022; 23: 1-11
• 39 Charles CA. Effect of arsenic trioxide poisoning on hematological parameters, liver marker enzymes and kidney of male albino rats. pinnacle biological sciences 2014; 2: 1-4
• 40 Kucukkurt I, Ince S, Demirel HH. et al. The Effects of Boron on Arsenic-Induced Lipid Peroxidation and Antioxidant Status in Male and Female Rats. Journal of Biochemical and Molecular Toxicology 2015; 29: 564-571
• 41 Mathews V, Paul M, Abhilash M. et al. Myocardial toxicity of acute promyelocytic leukaemia drug-arsenic trioxide. Eur Rev Med Pharmacol Sci 2013; 17: 34-38
• 42 Dávila-Esqueda M, Martinez-Morales F. Pentoxifylline diminishes the oxidative damage to renal tissue induced by streptozotocin in the rat. Experimental diabesity research 2004; 5: 245-251
• 43 Karimia J, Ranjbarb A, Tavilania H. Hepatoprotective effects of pentoxifylline against acrolein-induced mitochondrial dysfunction in rat liver. Journal of Reports in Pharmaceutical Sciences 2014; 3: 19-27
• 44 Gavella M, Lipovac V. Effect of pentoxifylline on experimentally induced lipid peroxidation in human spermatozoa. International journal of andrology 1994; 17: 308-313
• 45 Eğin S, Açıksarı K, Ercan G. et al. Effects of pentoxifylline on oxidative stress in rats with abdominal compartment syndrome model. International Journal of Surgery Open 2016; 5: 5-10
• 46 Neri M, Riezzo I, Pomara C. et al. Oxidative-nitrosative stress and myocardial dysfunctions in sepsis: evidence from the literature and postmortem observations. Mediators of Inflammation 2016; 2016: 1-12
• 47 Kesavan M, Sarath TS, Kannan K. et al. Atorvastatin restores arsenic-induced vascular dysfunction in rats: modulation of nitric oxide signaling and inflammatory mediators. Toxicology and applied pharmacology 2014; 280: 107-116
• 48 Bektas S, Karakaya K, Can M. et al. The effects of tadalafil and pentoxifylline on apoptosis and nitric oxide synthase in liver ischemia/reperfusion injury. The Kaohsiung Journal of Medical Sciences 2016; 32: 339-347
• 49 Hoebe KH, Gonzalez-Ramon N, Nijmeijer SM. et al. Differential effects of pentoxifylline on the hepatic inflammatory response in porcine liver cell cultures: Increase in inducible nitric oxide synthase expression. Biochemical pharmacology 2001; 61: 1137-1144
• 50 Li S, Tan H-Y, Wang N. et al. The role of oxidative stress and antioxidants in liver diseases. International journal of molecular sciences 2015; 16: 26087-26124
• 51 Han K-H, Hashimoto N, Fukushima M. Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes. World Journal of Gastroenterology 2016; 22: 37-49
• 52 Huchzermeyer B, Menghani E, Khardia P. et al. Metabolic pathway of natural antioxidants, antioxidant enzymes and ROS providence. Antioxidants 2022; 11: 761
• 53 Baş H, Kalender Y. Nephrotoxic effects of lead nitrate exposure in diabetic and nondiabetic rats: involvement of oxidative stress and the protective role of sodium selenite. Environmental Toxicology 2016; 31: 1229-1240
• 54 Liu B, Zhang H, Tan X. et al. GSPE reduces lead-induced oxidative stress by activating the Nrf2 pathway and suppressing miR153 and GSK-3β in rat kidney. Oncotarget 2017; 8: 42226-42237
• 55 Apaydın FG, Baş H, Kalender S. et al. Subacute effects of low dose lead nitrate and mercury chloride exposure on kidney of rats. Environmental toxicology and pharmacology 2016; 41: 219-224
• 56 Xu D, Zhao W, Feng Y. et al. Pentoxifylline attenuates nonalcoholic fatty liver by inhibiting hepatic macrophage polarization to the M1 phenotype. Phytomedicine 2022; 106: 154368
• 57 Tanideh R, Farshad O, Jamshidzadeh A. et al. Effects of Pentoxifylline in a Rat Model of Manganism: Evaluation of the Possible Toxicity. Journal of Chemistry 2021; 2021: 1-9
• 58 Gholami A, Ataei S, Ahmadimoghaddam D. et al. Pentoxifylline attenuates arsenic trioxide-induced cardiac oxidative damage in mice. Oxidative Medicine and Cellular Longevity 2021; 2021: 1-10