Protective effect of crocin on liver toxicity induced by morphine

Mohammad Reza Salahshoor, Mojtaba khashiadeh, Shiva Roshankhah, Seyran Kakabaraei, Cyrus Jalili


Crocin, a bioactive molecule of saffron can be purely isolated from the saffron extract. It has different pharmacological effects such as antioxidant and anticancer activities. Morphine is an opioid analgesic drug. It is mainly metabolized in liver and causes devastating effects. It can increase the generation of free radicals. This study was designed to evaluate the protective role of crocin against morphine-induced toxicity in the mouse liver. In this study, various doses of crocin (12.5, 25 and 50 mg/kg) and crocin plus morphine were administered interaperitoneally once daily to 48 male mice for 20 consecutive days. These mice were randomly assigned to 8 groups of 6 each. The liver weight and histology, aspartate amino transferase, alanine aminotransferase, alkaline phosphatase (ALP) and serum nitric oxide levels were studied. The results indicated that morphine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein diameters, liver enzyme levels, and blood serum nitric oxide level compared to saline group (P<0.05). However, crocin administration significantly boosted liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes and nitric oxide levels in all groups compared to the group received morphine alone (P<0.05). It seems that crocin administration could protect the liver damage induced by morphine. The antioxidant effect of crocin may be a major reason for its positive impact on liver parameters.

Full Text:



De Medeiros PM, Pinto BLS, Do Nascimento VT. Can organoleptic properties explain the differential use of medicinal plants? Evidence from North eastern Brazil. J. Ethnopharmacol. 2015;159:43-48.

Altinoz E, Oner Z, Elbe H, Cigremis Y, Turkoz Y. Protective effects of saffron (its active constituent, crocin) on nephropathy in streptozotocin-induced diabetic rats. Hum Exp Toxicol. 2015;34:127-134.

Amin A, Bajbouj K, Koch A, Gandesiri M, Schneider-Stock R. Defective autophagosome formation in p53-null colorectal cancer reinforces crocin-induced apoptosis. Int J Mol Sci. 2015;16:1544-1561.

Hosseinzadeh H, Shamsaie F, Mehri S. Antioxidant activity of aqueous and ethanolic extracts of Crocus sativus L. stigma and its bioactive constituent, Crocin and Safranal. Pharmacog Mag. 2009;5:419-424.

Hosseinzadeh H, Abootorabi A, Sadeghnia HR. Protective effect of Crocus sativus stigma extract and crocin (trans-crocin 4) on methyl methanesulfonate-induced DNA damage in mice organs. DNA Cell Biol. 2008;27:657-664.

Hosseinzadeh H, Shariaty MV, Sameni AK, Vahabzadeh M. Acute and sub-acute toxicity of crocin, a constituent of Crocus sativus L. (saffron), in mice and rats. Pharmacologyonline. 2010;2:943-951.

Seiri L, Mokri A, Dezhakam H, Noroozi A. Using tincture of opium for treatment of opiate abusers in Iran. Drug Alcohol Depend. 2014;140:e200.

Stoops WW, Hatton KW, Lofwall MR, Nuzzo PA, Walsh SL. Intravenous oxycodone, hydrocodone, and morphine in recreational opioid users: abuse potential and relative potencies. Psychopharmacology (Berl). 2010;212:193-203.

Asadi E, Shabani R, Ghafari S, Golalipour MJ. Preventing effect of vitamin E on oocytes apoptosis in morphine-treated mice. Int J Morphol. 2013;31:533-538.

Lan X, Rai P, Chandel N, Cheng K, Lederman R, Saleem MA, et al. Morphine induces albuminuria by compromising podocyte integrity. PloS one. 2013;8:e55748.

Mohammadi N, Bayati V, Nejatbakhsh R, Heidari MH, Dadpay M, Tavassol A. Effect of oral morphine on the liver of Wistar rat fetuses in the second week of development: a histopathological study. RJMS. 2015;21:1-9.

Mikus G, Klimas R. Relative contribution of morphine and morphine-6-glucuronide to the analgesic effect after morphine administration. Br J Anaesth. 2015;114:1007.

Samarghandian S, AfshariR, Farkhondeh T. Effect of long-term treatment of morphine on enzymes, oxidative stress indices and antioxidant status in male rat liver. Int J Clin Exp Med. 2014;7: 1449-1453.

Eslami H, Sharifi AM. Effect of carnosine on the prevention of high-dose morphine-induced apoptosis of PC12 Cells. J Med Bio. 2014;3:175-178.

Liu Y, Yang L, Tao K, Vizcaychipi M, Lloyd D, Sun X, et al. Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release. BMC Gastroenterol. 2014;14:12.

Chau N, Elliot DJ, Lewis BC, Burns K, Johnston MR, Mackenzie PI, et al. Morphine glucuronidation and glucosidation represent complementary metabolic pathways that are both catalyzed by UDP-glucuronosyl transferase 2B7: kinetic, inhibition, and molecular modeling studies. J Pharm Exp Ther. 2014;349:126-137.

Šlamberová R, Riley MA, Vathy I. Cross-generational effect of prenatal morphine exposure on neurobehavioral development of rat pups. Physiol Res. 2005;54:655-660.

jalili C, Salahshoor MR, Pourmotabbed A, Moradi S, Motaghi M, Roshankhah SH, et al. The Effects of Aqueous Extract of Boswellia Serrata on Hippocampal Region CA1 and learning deficit in kindled Rats. Res Pharm Sci. 2014;9:351-358.

Zhang YT, Zheng QS, Pan J, Zheng RL. Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Basic Clin Pharma Toxicol. 2004;95:53-58.

Lari P, Abnous K, Imenshahidi M, Rashedinia M, Razavi M, Hosseinzadeh H. Evaluation of diazinon-induced hepatotoxicity and protective effects of crocin. Toxicol. Ind. Health 2015;31: 367-376.

Basu S, Haldar N, Bhattacharya S, Biswas S, Biswas M. Hepatoprotective activity of Litchi chinensis leaf against paracetamol-induced liver damage in rats. Middlr East J Sci Res. 2014;20:292-296.

Zaitoun A, Apelqvist G, Al-Mardini H, Gray T, Bengtsson F, Record C. Quantitative studies of liver atrophy after portacaval shunt in the rat. J Surg Res. 2006;131:225-232.

Hematológico E. Action of trivalent chromium on rat liver structure. Histometric and haematological studies. Int J Morphol. 2006;24:197-203.

Jalili C, Salahshoor MR, Naderi T. The effect of hydroalcoholic extract of P. crispum on sperm parameters, testis tissue and serum nitric oxide levels in mice. Adv Biomed Res. 2015;4:40.

Reitman S, Frankel A. A colorimetric method for the determination of serum Glutamic oxaloacetic and Glutamic pyruvic transaminase. Am J Clin Path. 1957;28:56-63.

Sadashivam S, Manickam A. Biochemical methods. 2nd ed. Wiley Eastern Limited, New Delhi; 1996. p. 121-124.

Chen Y, Zhang H, Tian X, Zhao C, Cai L, Liu Y, et al. Antioxidant potential of crocins and ethanol extracts of Gardenia jasminoides ELLIS and Crocus sativus L: A relationship investigation between antioxidant activity and crocin contents. Food Chem. 2008;109:484-492.

Wang JQ, Zou YH, Cheng WM, Lu C, Zhang L. Preventive effects of total flavonoids of Litsea coreana leve on hepatic steatosis in rats fed with high fat diet. J Ethnopharmacol. 2009:121:54-60.

Drotman R, Lawhorn GT. Serum enzymes are indications of chemical induced liver damage. Drug Chem Toxicol. 1978;1:163-171.

Singh SP, Janecki AJ, Srivastava SK, Awasthi S, Awasthi YC, Xia SJ, et al. Mem-brane association of glutathione S-transferase mGSTA4-4, an enzyme that metabolizes lipid peroxidation products. J Biol Chem. 2002;277:4232-4239.

Samarghandian S, Afshari R, Farkhondeh T. Effect of long-term treatment of morphine on enzymes, oxidative stress indices and antioxidant status in male rat liver. Int J Clin Exp Med. 2014;7:1449-1453.

He SY, Tang FT, Wen N, Xu GL, Sheng L. Effect of crocin on experimental atherosclerosis in quails and its mechanisms. Life Sci. 2005;77:907-921.

Xiang M, Zhou CH, Liu J, Li WN. Crocetin inhibits leukocyte adherence to vascular endothelial cells induced by AGEs. J Ethnopharmacol. 2006;107: 25-31.

El-Maraghy SA, El-Sawalhi MM. Hepatoprotective potential of crocin and curcumin against iron overload-induced biochemical alterations in rat. Afr J Biochem Res. 2009:3:215-221.

Bekheet SH. Morphine sulphate induced histopathological and histochemical changes in the rat liver. Tissue Cell. 2010;42:266-272.

Todaka T, Ishida T, Kita H, Narimatsu S, Yamano S. Bioactivation of morphine in human liver: isolation and identification of morphinone, a toxic metabolite. Biol Pharm Bull. 2005;28:1275-1280.

Khayatnouri M, Safavi SE, Safarmashaei S, Babazadeh D, Mi¬kailpourardabili B. The effect of saffron orally administration on spermatogenesis index in rat. Adv Environ Biol. 2011;5:1514–1521.

Razavi M, Hosseinzadeh H, Abnous K, Motamedshariaty V, Imenshahidi M. Crocin restores hypotensive effect of subchronic administration of diazinon in rats. Iran J Basic Med Sci. 2013;16: 64-72.

Khorsandi LS, Taherimobarakeh M, Kalantari H. The protective effect of turmeric (curcuma longa) extract on acetaminophen induced liver damage in mice. J Zanjan Univ Med Sci. 2006;14:23-29.

Amouoghli Tabrizi B, Mohajeri D. Protective effect of edible turmeric powder on early hepatic injury in diabetic rats. J Kashan Univ Med Sci. 2010;14: 190-199.

Larrauri JA, Sánchez-Moreno C, Rupérez P, Saura-Calixto F. Free radical scavenging capacity in the aging of selected red Spanish wines. J Agric Food Chem. 1999;47:1603-1606.

Salahshoor M, Mohamadian S, Kakabaraei S, Roshankhah S, Jalili C. Curcumin improves liver damage in male mice exposed to nicotine. J Tradit Complement Med. 2015, In Press.

Hosseinzadeh H, Ziaee T, Danaee A. Protective effect of aqueous saffron extract (Crocus sativus L.) and crocin, its active constituent, on renal ischemia-reperfusion-induced oxidative damage in rats. J Pharm Pharm Sci. 2005;8:387-393.

Sakr SA. Ameliorative effect of Ginger (Zingiberofficinale) on mancozeb fungicide induced liver injury in albino rats. Aust J Basic Appl Sci. 2007;1:650-656.

Cordova C, Siqueira IR, Netto CA, Yunes RA, Volpato AM, Cechinel Filho V. Protective properties of butanolic extract of the Calendula officinalis L. against lipid peroxidation of rat liver microsomes and action as free radical scavenger. Redox Rep. 2002;7:95-102.

Mohajeri D, Doustar Y, Rezaei A, Mesgari-Abbasi M. Hepatoprotective effect of ethanolic extract of Crocus sativus L. (Saffron) stigma in comparison with silymarin against rifampin induced hepatotoxicity in rats. Zahedan J Res Med Sci. 2010;12:53-59.

Zaragoza A, Andrés D, Sarrión D, Cascales M. Potentiation of hioacetamide hepatotoxicity by phenobarbita retreatment in rats, inducibility of FAD monooxygenase system and age effect. Chem Biol Interact. 2000;124:87-101.

Hon W Lee KH, Khoo HE. Nitric oxide in liver diseases : friend, foe, or just passerby? Ann NY Acad Sci. 2002;962:275-295.

Zarrindast MR, Javadi-Paydar M, Delphi L, Vousooghi N. Morphine-induced nitric oxide production in PC12 Cells. Arch Iran Med. 2012;15:404-408.

Muller T, SchepersG. Evidence for peroxynitrite as an oxidative stress-inducing compound of aqueous cigarette smoke fraction. Carcinogenesis. 1997;18:295-301.


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.