Abstract
We have previously shown that oral administration of Nigella sativa oil (NSO) ameliorates the deleterious gastrointestinal effects of cisplatin (CP), administered as a single dose. Since a typical clinical CP dosing regimen involves multiple cycles of CP administration in lower doses, in the present study we investigate the protective efficacy of NSO and its major bioactive constituent, thymoquinone (TQ), against multiple-dose CP treatment-induced deleterious biochemical and histological changes in rat intestine. Rats were divided into six groups, viz., control, CP, CP+NSO, CP+TQ, NSO, and TQ. Animals in CP+NSO and CP+TQ groups were pre-administered NSO (2 ml/kg bwt, orally) and TQ (1.5 mg/kg bwt, orally), respectively, daily for 14 days and were then treated with five repeated doses of CP (3 mg/kg bwt, i.p.), every fourth day for 20 days while still receiving NSO/TQ. CP treatment alone led to a significant decline in specific activities of brush border membrane (BBM) enzymes while NSO or TQ administration to CP-treated rats significantly prevented the decline in BBM enzyme activities in the isolated brush border membrane vesicles (BBMV) as well as in mucosal homogenates. Furthermore, both NSO and TQ administration markedly ameliorated CP-induced alterations on carbohydrate metabolism enzymes and the enzymatic and non-enzymatic parameters of antioxidant defense system in the intestinal mucosa. However, NSO appeared to be more efficacious than TQ in protecting against CP-induced gastrointestinal dysfunction. Histopathological findings corroborated the biochemical results. Thus, NSO and TQ may prove clinically useful in amelioration of the intestinal toxicity associated with long-term CP chemotherapy.
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Abbreviations
- ACPase:
-
Acid phosphatase
- ALP:
-
Alkaline phosphatase
- BBM:
-
Brush border membrane
- BBMV:
-
BBM vesicles
- CAT:
-
Catalase
- CP:
-
Cisplatin
- FBPase:
-
Fructose 1,6-bisphosphatase
- G6Pase:
-
Glucose 6-phosphatase
- G6PDH:
-
Glucose 6-phosphate dehydrogenase
- GGTase:
-
γ-Glutamyl transferase
- GR:
-
Glutathione reductase
- GSH:
-
Glutathione reduced
- GSH-Px:
-
Glutathione peroxidase
- GST:
-
Glutathione S-transferase
- HK:
-
Hexokinase
- LAP:
-
Leucine aminopeptidase
- LDH:
-
Lactate dehydrogenase
- LPO:
-
Lipid peroxidation
- MDA:
-
Malondialdehyde
- MDH:
-
Malate dehydrogenase
- ME:
-
Malic enzyme
- NAD:
-
Nicotinamide adenine dinucleotide
- NADH:
-
Nicotinamide adenine dinucleotide reduced
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate reduced
- NADP:
-
Nicotinamide adenine dinucleotide phosphate
- NSO:
-
Nigella sativa oil
- ROS:
-
Reactive oxygen species
- SH:
-
Sulfhydryl
- SOD:
-
Superoxide dismutase
- TCA:
-
Tricarboxylic acid
- TQ:
-
Thymoquinone
- TR:
-
Thioredoxin reductase
References
Aggarwal SK (1993) A histochemical approach to the mechanism of action of cisplatin and its analogues. J Histochem Cytochem 41(7):1053–1073. https://doi.org/10.1177/41.7.8515048
Alenzi FQ, El-Bolkiny YE, Salem ML (2010) Protective effects of Nigella sativa oil and thymoquinone against toxicity induced by the anticancer drug cyclophosphamide. Br J Biomed Sci 67(1):20–28. https://doi.org/10.1080/09674845.2010.11730285
Ali BH, Blunden G (2003) Pharmacological and toxicological properties of Nigella sativa. Phytother Res 17(4):299–305. https://doi.org/10.1002/ptr.1309
Arivarasu NA, Fatima S, Mahmood R (2007) Effect of cisplatin on brush border membrane enzymes and anti-oxidant system of rat intestine. Life Sci 81(5):393–398. https://doi.org/10.1016/j.lfs.2007.06.001
Arivarasu NA, Priyamvada S, Mahmood R (2013) Oral administration of caffeic acid ameliorates the effect of cisplatin on brush border membrane enzymes and antioxidant system in rat intestine. Exp Toxicol Pathol 65(1-2):21–25. https://doi.org/10.1016/j.etp.2011.05.004
Badary OA, Awad AS, Sherief MA, Hamada FMA (2006) In vitro and in vivo effects of ferulic acid on gastrointestinal motility: inhibition of cisplatin-induced delay in gastric emptying in rats. World J Gastroenterol 12(33):5363–5367. https://doi.org/10.3748/wjg.v12.i33.5363
Badary OA, Nagi MN, Al-Shabanah OA, Al-Sawaf HA, Al-Sohaibani MO, Al-Bekairi AM (1997) Thymoquinone ameliorates the nephrotoxicity induced by cisplatin in rodents and potentiates its antitumor activity. Can J Physiol Pharmacol 75(12):1356–1361. https://doi.org/10.1139/y97-169
Cabezos PA, Vera G, Fontelles MIM, Pujol RF, Abalo R (2010) Cisplatin-induced gastrointestinal dysmotility is aggravated after chronic administration in the rat. Comparison with pica. Neurogastroenterol Motil 22(7):797–805. https://doi.org/10.1111/j.1365-2982.2010.01483.x
Carlberg I, Mannervik B (1985) Glutathione reductases. Methods Enzymol 113:484–490. https://doi.org/10.1016/S0076-6879(85)13062-4
Carrillo-Tripp M, Feller SE (2005) Evidence for a mechanism by which omega-3 polyunsaturated lipids may affect membrane protein function. Biochemistry 44(30):10164–10169. https://doi.org/10.1021/bi050822e
Chang B, Nishikawa M, Sato E, Utsumi K, Inoue M (2002) L-Carnitine inhibits cisplatin induced injury of the kidney and small intestine. Arch Biochem Biophys 405(1):55–64. https://doi.org/10.1016/S0003-9861(02)00342-9
Crane RK, Sols A (1953) The association of particulate fractions of brain and other tissue homogenates. J Biol Chem 203(1):273–292
Darakhshan S, Poura AB, Colagar AH, Sisakhtnezhad S (2015) Thymoquinone and its therapeutic potentials. Pharmacol Res 95-96:138–158. https://doi.org/10.1016/j.phrs.2015.03.011
DeWoskin RS, Riviere JE (1992) Cisplatin-induced loss of kidney copper and nephrotoxicity is ameliorated by single dose diethyldithiocarbamate, but not mesna. Toxicol Appl Pharmacol 112(2):182–189. https://doi.org/10.1016/0041-008X(92)90186-V
El-Abhar HS, Abdallah DM, Saleh S (2003) Gastroprotective activity of Nigella sativa oil and its constituent, thymoquinone, against gastric mucosal injury induced by ischaemia/reperfusion in rats. J Ethnopharmacol 84(2-3):251–258. https://doi.org/10.1016/S0378-8741(02)00324-0
Farooq N, Yusufi ANK, Mahmood R (2004) Effect of fasting on enzymes of carbohydrate metabolism and brush border membrane in rat intestine. Nutr Res 24(6):407–416. https://doi.org/10.1016/j.nutres.2004.01.004
Farooqui Z, Afsar M, Rizwan S, Khan AA, Khan F (2016) Oral administration of Nigella sativa oil ameliorates the effect of cisplatin on membrane enzymes, carbohydrate metabolism and oxidative damage in rat liver. Toxicol Rep 3:328–335. https://doi.org/10.1016/j.toxrep.2016.02.004
Farooqui Z, Ahmed F, Rizwan S, Shahid F, Khan AA, Khan F (2017) Protective effect of Nigella sativa oil on cisplatin induced nephrotoxicity and oxidative damage in rat kidney. Biomed Pharmacother 85:7–15. https://doi.org/10.1016/j.biopha.2016.11.110
Flohe L, Gunzler W (1984) Assays of glutathione peroxidase. In: Colowick, S.P., Kaplan, N.O. (Eds.). Methods Enzymol. Academic Press, New York 105:114–121
Gali-Muhtasib H, Ocker M, Kuester D, Krueger S, El-Hajj Z, Diestel A, Evert M, El-Najjar N, Peters B, Jurjus A, Roessner A, Schneider-Stock R (2008) Thymoquinone reduces mouse colon tumor cell invasion and inhibits tumor growth in murine colon cancer models. J Cell Mol Med 12(1):330–342. https://doi.org/10.1111/j.1582-4934.2007.00095.x
Gholamnezhad Z, Havakhah S, Boskabady MH (2016) Preclinical and clinical effects of Nigella Sativa and its constituent, thymoquinone: a review. J Ethnopharmacol 190:372–386. https://doi.org/10.1016/j.jep.2016.06.061
Gholamnezhad Z, Keyhanmanesh R, Boskabady MH (2015) Anti-inflammatory, antioxidant, and immunomodulatory aspects of Nigella sativa for its preventive and bronchodilatory effects on obstructive respiratory diseases: a review of basic and clinical evidence. J Funct Foods 17:910–927. https://doi.org/10.1016/j.jff.2015.06.032
Giri U, Iqbal M, Athar M (1996) Porphyrin mediated photosensitization has a weak tumor promoting activity in mouse skin: possible role of in-situ generated reactive oxygen species. Carcinogenesis 17(9):2023–2028. https://doi.org/10.1093/carcin/17.9.2023
Glossmann H, Neville DM (1972) Gamma-glutamyltransferase in kidney brush border membranes. FEBS Lett 19(4):340–344. https://doi.org/10.1016/0014-5793(72)80075-9
Goldmann DR, Schlesinger H, Segal S (1976) Isolation and characterization of the brush border fraction from new born rat renal proximal tubule cells. Biochim Biophys Acta 419(2):251–260. https://doi.org/10.1016/0005-2736(76)90351-5
Goldstein A, Lampen JP (1975) Beta-d-fructofuranoside fructohydrolase from yeast. Methods Enzymol 42:504–511. https://doi.org/10.1016/0076-6879(75)42159-0
Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. J Biol Chem 249(22):7130–7139
Hosseinzadeh H, Parvardeh S, Asl MN, Sadeghnia HR, Ziaee T (2007) Effect of thymoquinone and Nigella sativa seeds oil on lipid peroxidation level during global cerebral ischemia-reperfusion injury in rat hippocampus. Phytomedicine 14(9):621–627. https://doi.org/10.1016/j.phymed.2006.12.005
Ismail M, Al-naqeep G, Chan KW (2009) Nigella sativa thymoquinone-rich fraction greatly improves plasma antioxidant capacity and expression of antioxidant genes in hypercholesterolemic rats. Free Radic Biol Med 48(5):664–672. https://doi.org/10.1016/j.freeradbiomed.2009.12.002
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. Pharmacology 11(3):151–169. https://doi.org/10.1159/000136485
Kanter M, Demir H, Karakaya C, Ozbek H (2005) Gastroprotective activity of Nigella sativa L oil and its constituent, thymoquinone against acute alcohol-induced gastric mucosal injury in rats. World J Gastroenterol 11(42):6662–6666. https://doi.org/10.3748/wjg.v11.i42.6662
Khan R, Khan AQ, Qamar W, Lateef A, Tahir M, Rehman MU, Ali F, Sultana S (2012) Chrysin protects against cisplatin-induced colon toxicity via amelioration of oxidative stress and apoptosis: probable role of p38MAPK and p53. Toxicol Appl Pharmacol 258(3):315–329. https://doi.org/10.1016/j.taap.2011.11.013
Khan SA, Priyamvada S, Farooq N, Khan S, Khan MW, Yusufi ANK (2009) Protective effect of green tea extract on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney. Pharmacol Res 59(4):254–262. https://doi.org/10.1016/j.phrs.2008.12.009
Khundmiri SJ, Asghar M, Khan F, Salim S, Yusufi ANK (2004) Effect of ischemia and reperfusion on enzymes of carbohydrate metabolism in rat kidney. J Nephrol 17(3):377–383
Kuhlmann MK, Burkhardt G, Kohler H (1997) Insights into potential cellular mechanisms of cisplatin nephrotoxicity and their clinical application. Nephrol Dial Transplant 12(12):2478–2480. https://doi.org/10.1093/ndt/12.12.2478
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275
Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autooxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47(3):469–474. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x
Naqshbandi A, Rizwan S, Khan MW, Khan F (2013) Dietary flaxseed oil supplementation ameliorates the effect of cisplatin on brush border membrane enzymes and antioxidant system in rat intestine. Hum Exp Toxicol 32(4):385–394. https://doi.org/10.1177/0960327112438929
Nelson NA (1944) Photometric adaptation of the Somogyi method for the determination of glucose. J Biol Chem 153:375–381
Ohkawa H, Ohishi N, Yagi N (1979) Assay for lipid peroxides in animal tissues bythiobarbituric acid reaction. Anal Biochem 95(2):351–358. https://doi.org/10.1016/0003-2697(79)90738-3
Pini A, Garella R, Idrizaj E, Calosi L, Baccari MC, Vannucchi MG (2016) Glucagon-like peptide 2 counteracts the mucosal damage and the neuropathy induced by chronic treatment with cisplatin in the mouse gastric fundus. Neurogastroenterol Motil 28(2):206–216. https://doi.org/10.1111/nmo.12712
Raghavendran HRB, Rekha S, Shin JW, Kim HG, Wang JH, Park HJ, Choi MK, Cho JH, Son CG (2011) Effects of Korean ginseng root extract on cisplatin-induced emesis in a rat-pica model. Food Chem Toxicol 49(1):215–221. https://doi.org/10.1016/j.fct.2010.10.019
Sedlak J, Lindsay RH (1968) Estimation of total protein bound and non protein bound SH groups in tissue with Ellman’s reagent. Anal Biochem 2:192–205
Shahid F, Farooqui Z, Rizwan S, Abidi S, Parwez I, Khan F (2017) Oral administration of Nigella sativa oil ameliorates the effect of cisplatin on brush border membrane enzymes, carbohydrate metabolism and antioxidant system in rat intestine. Exp Toxicol Pathol 69(5):299–306. https://doi.org/10.1016/j.etp.2017.02.001
Shahraki S, Khajavirad A, Shafei MN, Mahmoudi M, Tabasi NS (2015) Effect of total hydroalcholic extract of Nigella sativa and its n-hexane and ethyl acetate fractions on ACHN and GP-293 cell lines. J Tradit Complement Med 6(1):89–96. https://doi.org/10.1016/j.jtcme.2014.11.018
Tamura T, Stadtman TC (1996) A new selenoprotein from human lung adenocarcinoma cells: purification, properties and thioredoxin reductases activity. Proc Natl Acad Sci U S A 93(3):1006–1011. https://doi.org/10.1073/pnas.93.3.1006
Valentovic MA, Ball JG, Brown JM, Terneus MV, McQuade E, Meter SV, Hedrick HM, Roy AA, Williams T (2014) Resveratrol attenuates cisplatin renal cortical cytotoxicity by modifying oxidative stress. Toxicol In Vitro 28:248–257
Vera G, Chiarlone A, Cabezos PA, Pascual D, Martín MI, Abalo R (2007) WIN 55,212-2 prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat. Life Sci 81(6):468–479. https://doi.org/10.1016/j.lfs.2007.06.012
Yehuda S, Carasso RL (1993) Modulation of learning, pain thresholds, and thermoregulation in the rat by preparations of free purified alpha-linolenic and linoleic acids: determination of the optimal omega 3-to-omega 6 ratio. Proc Natl Acad Sci U S A 90(21):10345–10349. https://doi.org/10.1073/pnas.90.21.10345
Youdim KA, Martin A, Joseph JA (2000) Essential fatty acids and the brain: possible health implications. Int J Dev Neurosci 18(4-5):383–399. https://doi.org/10.1016/S0736-5748(00)00013-7
Yusufi ANK, Low MG, Turner SP, Dousa TP (1983) Selective removal of alkaline phosphatase from renal brush-border membrane and sodium-dependent brush-border membrane transport. J Biol Chem 258(9):5695–5701
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The authors gratefully acknowledge the University Grants Commission (UGC), New Delhi, for the award of Senior Research Fellowship (under MANF scheme) to F.S and Z.F.
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Animal experiments were permitted by the Ministry of Environment, Forests and Climate Change, Government of India, under registration no. 714/GO/Re/02/CPCSEA issued by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) dated 29th October 2014 and approved by the Institutional Animal Ethic Committee (IAEC) of the Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India.
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Shahid, F., Farooqui, Z., Khan, A.A. et al. Oral Nigella sativa oil and thymoquinone administration ameliorates the effect of long-term cisplatin treatment on the enzymes of carbohydrate metabolism, brush border membrane, and antioxidant defense in rat intestine. Naunyn-Schmiedeberg's Arch Pharmacol 391, 145–157 (2018). https://doi.org/10.1007/s00210-017-1444-6
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DOI: https://doi.org/10.1007/s00210-017-1444-6