Infliximab Modulates Cisplatin-Induced Hepatotoxicity in Rats

Abstract

Background: Cisplatin (Cis) is one of the most commonly used antineoplastic drugs. It is used as chemotherapy for many solid organ malignancies such as brain, neck, male and female urogenital, vesical and pulmonary cancers. Infliximab blocks tumor necrosis factor alpha (TNF-α). Several studies have reported that infliximab ameliorates cell damage by reducing cytokine levels. Aims: We aimed to investigate whether infliximab has a preventive effect against cisplatin-induced hepatotoxicity and whether it has a synergistic effect when combined with Cis. Study Design: Animal experimentation. Methods: Male Wistar albino rats were divided in three groups as follows: Cis group, infliximab + Cis (CIN) group and the control group. Each group comprised 10 animals. Animals in the Cis group received an intraperitoneal single-dose injection of Cis (7 mg/kg). In the CIN group, a single dose of infliximab (7 mg/kg) was administered 72 h prior to the Cis injection. After 72 h, a single dose of Cis (7 mg/kg) was administered. All rats were sacrificed five days after Cis injection. Results: TNF-α levels in the Cis group were significantly higher (345.5±40.0 pg/mg protein) than those of the control (278.7±62.1 pg/mg protein, p=0.003) and CIN groups (239.0±64.2 pg/mg protein, p=0.013). The Cis group was found to have high carbonic anhydrase (CA)-II and low carbamoyl phosphate synthetase-1 (CPS-1) levels. Aspartate transaminase (AST) and alanine transaminase (ALT) levels were lower in the CIN group as compared to the Cis group. Total histological damage was greater in the Cis group as compared to the control and CIN groups. Conclusion: Cis may lead to liver damage by increasing cytokine levels. It may increase oxidative stress-induced tissue damage by increasing carbonic anhydrase II (CA-II) enzyme levels and decreasing CPS-1 enzyme levels. Infliximab decreases Cis-induced hepatic damage by blocking TNF-α and  it may also protect against liver damage by regulating CPS-1 and CA-II enzyme levels.

Keywords

• Carbamoyl-phosphate synthetase 1, carbonic anhydrase, cisplatin, hepatotoxicity, infliximab, tumor necrosis factor alpha

Kaynakça

1. 1. Bentli R, Parlakpinar H, Polat A, Samdanci E, Sarihan ME, Sagir M. Molsidomine prevents cisplatin-induced hepatotoxicity. Arch Med Res 2013;44:521-28. [CrossRef]
2. 2. Waseem M, Parvez S. Mitochondrial dysfunction mediated cisplatin induced toxicity: modulatory role of curcumin. Food Chem Toxicol 2013;53:334-42. [CrossRef]
3. 3. Karadeniz A, Simsek N, Karakus E, Yildirim S, Kara A, Can I, et al. Royal jelly modulates oxidative stress and apoptosis in liver and kidneys of rats treated with cisplatin. Oxid Med Cell Longev 2011;981793. [CrossRef]
4. 4. Ferah I, Halici Z, Bayir Y, Demirci E, Unal B, Cadirci E. The role of infliximab on paracetamol-induced hepatotoxicity in rats. Immunopharmacol Immunotoxicol 2013;35:373-81. [CrossRef]
5. 5. Mahmoud MF, El Shazly SM, Barakat W. Inhibition of TNF-α protects against hepatic ischemia-reperfusion injury in rats via NF-κB dependent pathway. Naunyn Schmiedebergs Arch Pharmacol 2012;385:465-71. [CrossRef]
6. 6. Amanzada A, Moriconi F, Mansuroglu T, Cameron S, Ramadori G, Malik IA. Induction of chemokines and cytokines before neutrophils and macrophage recruitment in different regions of rat liver after TAA administration. Lab Invest 2014;94:235-47. [CrossRef]
7. 7. Cure E, Kirbas A, Tumkaya L, Cure MC, Kalkan Y, Yilmaz A, et al. Protective effect of infliximab on methotrexate-induced liver injury in rats: Unexpected drug interaction. J Cancer Res Ther 2015;11:164-9. [CrossRef]
8. 8. Sehitoglu I, Tumkaya L, Bedir R, Ozer E, Cure MC, Kalkan Y, et al. Protective Effect of Infliximab Against Carbon Tetrachloride-Induced Hepatotoxicity. J Environ Pathol Toxicol Oncol 2015;34:175-82. [CrossRef]

9. 9. Shah GN, Rubbelke TS, Hendin J, Nguyen H, Waheed A, Shoemaker JD, et al. Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism. Proc Natl Acad Sci USA 2013;110:7423-8. [CrossRef]
10. 10. Lapenna D, Ciofani G, Cuccurullo C, Neri M, Giamberardino MA, Cuccurullo F. Bicarbonate-dependent, carbonate radical anion-driven tocopherol-mediated human LDL peroxidation: an in vitro and in vivo study. Free Radic Res 2012;46:1387-92. [CrossRef]
11. 11. Cure E, Kirbas A, Tumkaya L, Cure MC, Sahin OZ, Kalkan Y, et al. Effect of infliximab against cisplatin-induced nephrotoxicity. Saudi Med J 2014;35:953-8.
12. 12. Diez-Fernandez C, Martinez AI, Pekkala S, Barcelona B, PerezArellano I, Guadalajara AM, et al. Molecular characterization of carbamoyl-phosphate synthetase (CPS1) deficiency using human recombinant CPS1 as a key tool. Hum Mutat 2013;34:1149- 59. [CrossRef]
13. 13. Santi A, Caselli A, Paoli P, Corti D, Camici G, Pieraccini G, et al. The effects of CA IX catalysis products within tumor microenvironment. Cell Commun Signal 2013;11:81. [CrossRef]
14. 14. Cayır K, Karadeniz A, Simşek N, Yıldırım S, Karakuş E, Kara A, et al. Pomegranate seed extract attenuates chemotherapyinduced acute nephrotoxicity and hepatotoxicity in rats. J Med Food 2011;14:1254-62. [CrossRef]
15. 15. Cure E, Cumhur Cure M, Tumkaya L, Kalkan Y, Aydin I, Kirbas A, et al. Adalimumab ameliorates abdominal aorta cross clamping which induced liver injury in rats. Biomed Res Int 2014;2014:907915. [CrossRef]
16. 16. Cure E, Cure MC, Tumkaya L, Kalkan Y, Aydin I, Kirbas A, et al. Topiramate ameliorates abdominal aorta cross-clamping induced liver injury in rats. Saudi J Gastroenterol 2014;20:297- 303. [CrossRef