PDF herunterladen
Drug Res (Stuttg) 2016; 66(09): 470-478
DOI: 10.1055/s-0042-110178
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Triazole rizatriptan Induces Liver Toxicity through Lysosomal/Mitochondrial Dysfunction

J. K. Fard
1   Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
2   Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3   Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
4   Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
,
H. Hamzeiy
2   Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3   Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
,
M. Sattari
2   Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3   Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
,
A. Eftekhari
2   Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3   Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
,
E. Ahmadian
2   Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3   Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
,
M. A. Eghbal
2   Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3   Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 28. Januar 2016

accepted 07. Juni 2016

Publikationsdatum:
11. Juli 2016 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Background: Triptans are used as antimigraine agents. Some cases of hepatotoxicity by triptans have been reported. However, the exact mechanism of triptan-induced hepatotoxicity is not clear yet.

Methods: In this study, the cytotoxic effects of rizatriptan were investigated in freshly isolated rat hepatocytes using accelerated cytotoxicity mechanism screening. We designed experiments to evaluate toxicity markers, such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, lysosomal membrane integrity and the amount of reduced and oxidized glutathione in the rizatriptan-treated hepatocytes.

Results: Cytotoxicity caused by rizatriptan in rat hepatocytes was concentration-dependent. An increase in ROS formation accompanied by a significant rise in lipid peroxidation, mitochondrial depolarization and loss of lysosomal membrane integrity was observed. Cellular glutathione reservoirs were decreased and a significant amount of oxidized glutathione was formed. All the aforementioned rizatriptan-induced cellular events were significantly (p<0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Also, the present results demonstrated that CYP450 is involved in rizatriptan-induced oxidative stress and cytotoxicity mechanism and different CYP450 inducers had different effects on the toxicity.

Conclusion: It is suggested that the adverse effect of rizatriptan towards hepatocytes is mediated by oxidative stress and the hepatocytes lysosomes and mitochondria play an important role in rizatriptan-induced cell injury.

Key words

oxidative stress - reactivity oxygen species - hepatotoxicity - rizatriptan - lysosome - mitochondria
 

  • References

  • 1 Prasa D, Reinecke H, Rauber-Lüthy C et al. Overdose of selective serotonin (5HT1) agonists. Hypertension 2012; 4: 5
    PubMedSuche in Google Scholar
  • 2 Fernandez-Atutxa A. First report of toxic hepatitis: case report. Reactions 2013; 1453: 25
    PubMedSuche in Google Scholar
  • 3 Fernandez-Atutxa A, Vergara M, Gil M et al. Hepatotoxicidad de rizatriptán. Descripción de un caso clínico. Gastroenterol Hepatol 2013; 36: 261-263
    CrossrefPubMedSuche in Google Scholar
  • 4 Fulton JA, Kahn J, Nelson LS et al. Renal infarction during the use of rizatriptan and zolmitriptan: two case reports. Clin Toxicol 2006; 44: 177-180
    CrossrefPubMedSuche in Google Scholar
  • 5 Malacarne S, Moll S, Hadaya K et al. Renal ischaemic injuries during the use of zolmitriptan for treatment of migraines in a transplanted patient under tacrolimus therapy. Nephrology Dialysis Transplantation 2007; 22: 3341-3343
    CrossrefPubMedSuche in Google Scholar
  • 6 Larivière I, Garat A, Nisse P et al. Pediatric poisoning with triptans: review of cases in the Lille poison center between 2000 and 2010. Archives de pediatrie: organe officiel de la Societe francaise de pediatrie 2012; 19: 254-259
    PubMedSuche in Google Scholar
  • 7 Kaludercic N, Mialet-Perez J, Paolocci N et al. Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 2014; 73: 34-42
    CrossrefPubMedSuche in Google Scholar
  • 8 Cohen G, Kesler N. Monoamine oxidase and mitochondrial respiration. J Neurochem 1999; 73: 2310-2315
    PubMedSuche in Google Scholar
  • 9 Edmondson DE. Hydrogen peroxide produced by mitochondrial monoamine oxidase catalysis: biological implications. Curr Pharm Des 2014; 20: 155-160
    CrossrefPubMedSuche in Google Scholar
  • 10 Poon CCW, Seto SW, Au ALS et al. Mitochondrial monoamine oxidase-A-mediated hydrogen peroxide generation enhances 5-hydroxytryptamine-induced contraction of rat basilar artery. Br J Pharmacol 2010; 161: 1086-1098
    CrossrefPubMedSuche in Google Scholar
  • 11 Rotella P. Analogue-based Drug Discovery III. CHEMISTRY International 2013;
    PubMedSuche in Google Scholar
  • 12 Armstrong SC, Cozza KL. Triptans. Psychosomatics 2002; 43: 502-504
    CrossrefPubMedSuche in Google Scholar
  • 13 Ohkuma S, Poole B. Cytoplasmic vacuolation of mouse peritoneal macrophages and the uptake into lysosomes of weakly basic substances. The Journal of cell biology 1981; 90: 656-664
    CrossrefPubMedSuche in Google Scholar
  • 14 Vyas KP, Halpin RA, Geer LA et al. Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, in humans. Drug Metab Disposition 2000; 28: 89-95
    PubMedSuche in Google Scholar
  • 15 Hsu C-c, Lin C-c, Liao T-s et al. Protective effect of s-allyl cysteine and s-propyl cysteine on acetaminophen-induced hepatotoxicity in mice. Food Chem Toxicol 2006; 44: 393-397
    CrossrefPubMedSuche in Google Scholar
  • 16 Yu F-Y, Wu T-S, Chen T-W et al. Aristolochic acid I induced oxidative DNA damage associated with glutathione depletion and ERK1/2 activation in human cells. Toxicol In Vitro 2011; 25: 810-816
    CrossrefPubMedSuche in Google Scholar
  • 17 Butterworth RF. Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure. J Clin Exp Hepatol 2015; 5: S96-S103
    CrossrefPubMedSuche in Google Scholar
  • 18 Abdoli N, Azarmi Y, Eghbal MA. Protective effects of N-acetylcysteine against the statins cytotoxicity in freshly isolated rat hepatocytes. Advanced pharmaceutical bulletin 2014; 4: 249
    PubMedSuche in Google Scholar
  • 19 Reddy PS, Rani GP, Sainath S et al. Protective effects of N-acetylcysteine against arsenic-induced oxidative stress and reprotoxicity in male mice. J Trace Elem Med Biol 2011; 25: 247-253
    CrossrefPubMedSuche in Google Scholar
  • 20 Wong CK, Ooi VE, Wong CK. Protective effects of N-acetylcysteine against carbon tetrachloride-and trichloroethylene-induced poisoning in rats. Environ Toxicol Pharmacol 2003; 14: 109-116
    CrossrefPubMedSuche in Google Scholar
  • 21 Sinha M, Manna P, Sil PC. Taurine, a conditionally essential amino acid, ameliorates arsenic-induced cytotoxicity in murine hepatocytes. Toxicol In Vitro 2007; 21: 1419-1428
    CrossrefPubMedSuche in Google Scholar
  • 22 Zhao L, Lou J, Kang Y. Taurine-magnesium coordination compound attenuates hypoxia/reoxygenation induced ion channel dysfunction in rat ventricular myocytes. Drug research 2013; 63: 185-191
    Thieme ConnectPubMedSuche in Google Scholar
  • 23 Rashid K, Das J, Sil PC. Taurine ameliorate alloxan induced oxidative stress and intrinsic apoptotic pathway in the hepatic tissue of diabetic rats. Food Chem Toxicol 2013; 51: 317-329
    CrossrefPubMedSuche in Google Scholar
  • 24 Das J, Ghosh J, Manna P et al. Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. Toxicology 2010; 269: 24-34
    CrossrefPubMedSuche in Google Scholar
  • 25 Eghbal MA, Taziki S, Sattari MR. Mechanisms of Phenytoin-Induced Toxicity in Freshly Isolated Rat Hepatocytes and the Protective Effects of Taurine and/or Melatonin. J Biochem Mol Toxicol 2014; 28: 111-118
    CrossrefPubMedSuche in Google Scholar
  • 26 Eghbal MA, Taziki S, Sattari MR et al. Protective role of melatonin and taurine against carbamazepine-induced toxicity in freshly isolated rat hepatocytes. Int J Morphol 2013; 31: 1081-1089
    CrossrefPubMedSuche in Google Scholar
  • 27 Hagar HH. The protective effect of taurine against cyclosporine A-induced oxidative stress and hepatotoxicity in rats. Toxicol Lett 2004; 151: 335-343
    CrossrefPubMedSuche in Google Scholar
  • 28 Heidari R, Babaei H, Eghbal MA. Ameliorative effects of taurine against methimazole-induced cytotoxicity in isolated rat hepatocytes. Sci Pharm 2012; 80: 987
    CrossrefPubMedSuche in Google Scholar
  • 29 Taziki S, Sattari MR, Eghbal MA. Evaluation of amitriptyline-induced toxicity in freshly isolated rat hepatocytes and the protective role of taurine. Life Sci J 2013; 10: 314-320
    PubMedSuche in Google Scholar
  • 30 Taziki S, Sattari MR, Eghbal MA. Mechanisms of Trazodone-Induced Cytotoxicity and the Protective Effects of Melatonin and/or Taurine toward Freshly Isolated Rat Hepatocytes. J Biochem Mol Toxicol 2013; 27: 457-462
    PubMedSuche in Google Scholar
  • 31 El Dib R, Soliman H, Hussein M et al. Two New Flavonoids and Biological Activity of Astragalus abyssinicus (Hochst.) Steud. ex A. Rich. Aerial Parts. Drug research 2015; 65: 259-265
    Thieme ConnectPubMedSuche in Google Scholar
  • 32 Russo M, Spagnuolo C, Tedesco I et al. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol 2012; 83: 6-15
    CrossrefPubMedSuche in Google Scholar
  • 33 Panchal SK, Poudyal H, Brown L. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. The Journal of nutrition 2012; 142: 1026-1032
    CrossrefPubMedSuche in Google Scholar
  • 34 Padma VV, Baskaran R, Roopesh RS et al. Quercetin attenuates lindane induced oxidative stress in wistar rats. Mol Biol Rep 2012; 39: 6895-6905
    CrossrefPubMedSuche in Google Scholar
  • 35 Chen X. Protective effects of quercetin on liver injury induced by ethanol. Pharmacogn Mag 2010; 6: 135
    CrossrefPubMedSuche in Google Scholar
  • 36 Mostafavi-Pour Z, Zal F, Monabati A et al. Protective effects of a combination of quercetin and vitamin E against cyclosporine A-induced oxidative stress and hepatotoxicity in rats. Hepatology Research 2008; 38: 385-392
    CrossrefPubMedSuche in Google Scholar
  • 37 Nabavi SM, Nabavi SF, Eslami S et al. In vivo protective effects of quercetin against sodium fluoride-induced oxidative stress in the hepatic tissue. Food Chem 2012; 132: 931-935
    CrossrefPubMedSuche in Google Scholar
  • 38 Yousef MI, Omar SA, El-Guendi MI et al. Potential protective effects of quercetin and curcumin on paracetamol-induced histological changes, oxidative stress, impaired liver and kidney functions and haematotoxicity in rat. Food Chem Toxicol 2010; 48: 3246-3261
    CrossrefPubMedSuche in Google Scholar
  • 39 Gultekin F, Delibas N, Yasar S et al. In vivo changes in antioxidant systems and protective role of melatonin and a combination of vitamin C and vitamin E on oxidative damage in erythrocytes induced by chlorpyrifos-ethyl in rats. Arch Toxicol 2001; 75: 88-96
    CrossrefPubMedSuche in Google Scholar
  • 40 Rezaei-Basiri M, Rezazadeh H, Asvadi-Kermani I et al. Antimutagenic Effects of Vitamin E on Oncology and Non Oncology Hospital Nurses by Comet Assay. Drug research 2014; 64: 337-342
    Thieme ConnectPubMedSuche in Google Scholar
  • 41 Eskandari MR, Pourahmad J, Daraei B. Thallium (I) and thallium (III) induce apoptosis in isolated rat hepatocytes by alterations in mitochondrial function and generation of ROS. Toxicological and Environ Chemistry 2011; 93: 145-156
    CrossrefPubMedSuche in Google Scholar
  • 42 Pourahmad J, Eskandari MR, Kaghazi A et al. A new approach on valproic acid induced hepatotoxicity: involvement of lysosomal membrane leakiness and cellular proteolysis. Toxicol In Vitro 2012; 26: 545-551
    CrossrefPubMedSuche in Google Scholar
  • 43 Mostafalou S, Abdollahi M, Eghbal MA et al. Protective effect of NAC against malathion-induced oxidative stress in freshly isolated rat hepatocytes. Advanced pharmaceutical bulletin 2012; 2: 79
    PubMedSuche in Google Scholar
  • 44 Fard JK, Jafari S, Eghbal MA. A Review of Molecular Mechanisms Involved in Toxicity of Nanoparticles. Advanced Pharmaceutical Bulletin 2015; 5: 447-454
    CrossrefPubMedSuche in Google Scholar
  • 45 Khan S, O'Brien PJ. 1-Bromoalkanes as new potent nontoxic glutathione depletors in isolated rat hepatocytes. Biochem Biophys Res Commun 1991; 179: 436-441
    CrossrefPubMedSuche in Google Scholar
  • 46 Heidari R, Babaei H, Eghbal MA. Cytoprotective effects of taurine against toxicity induced by isoniazid and hydrazine in isolated rat hepatocytes. Archives of Industrial Hygiene and Toxicology 2013; 64: 201-210
    PubMedSuche in Google Scholar
  • 47 Eskandari MR, Fard JK, Hosseini M-J et al. Glutathione mediated reductive activation and mitochondrial dysfunction play key roles in lithium induced oxidative stress and cytotoxicity in liver. BioMetals 2012; 25: 863-873
    CrossrefPubMedSuche in Google Scholar
  • 48 Reed D, Babson J, Beatty P et al. High-performance liquid chromatography analysis of nanomole levels of glutathione, glutathione disulfide, and related thiols and disulfides. Anal Biochem 1980; 106: 55-62
    CrossrefPubMedSuche in Google Scholar
  • 49 Eskandari MR, Moghaddam F, Shahraki J et al. A comparison of cardiomyocyte cytotoxic mechanisms for 5-fluorouracil and its pro-drug capecitabine. Xenobiotica 2014; 45: 79-87
    PubMedSuche in Google Scholar
  • 50 Bernecker C, Ragginer C, Fauler G et al. Oxidative stress is associated with migraine and migraine-related metabolic risk in females. Eur J Neurol 2011; 18: 1233-1239
    CrossrefPubMedSuche in Google Scholar
  • 51 Shatillo A, Koroleva K, Giniatullina R et al. Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system. Neuroscience 2013; 253: 341-349
    CrossrefPubMedSuche in Google Scholar
  • 52 Holmström KM, Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nature Reviews Molecular Cell Biology 2014; 15: 411-421
    CrossrefPubMedSuche in Google Scholar
  • 53 Valko M, Leibfritz D, Moncol J et al. Free radicals and antioxidants in normal physiological functions and human disease. The international journal of biochemistry & cell biology 2007; 39: 44-84
    CrossrefPubMedSuche in Google Scholar
  • 54 Barrera G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol 2012; 2012
    PubMedSuche in Google Scholar
  • 55 Anderson EJ, Katunga LA, Willis MS. Mitochondria as a source and target of lipid peroxidation products in healthy and diseased heart. Clin Exp Pharmacol Physiol 2012; 39: 179-193
    CrossrefPubMedSuche in Google Scholar
  • 56 Bütün A, Nazıroğlu M, Demirci S et al. Riboflavin and vitamin E increase brain calcium and antioxidants, and microsomal calcium-ATP-ase values in rat headache models induced by glyceryl trinitrate. The Journal of membrane biology 2015; 248: 205-213
    CrossrefPubMedSuche in Google Scholar
  • 57 Eren Y, Dirik E, Neşelioğlu S et al. Oxidative stress and decreased thiol level in patients with migraine: cross-sectional study. Acta Neurol Belg 2015; 115: 643-649
    CrossrefPubMedSuche in Google Scholar
  • 58 Yorns WR, Hardison HH. Mitochondrial dysfunction in migraine. Semin Pediatr Neurol: Elsevier 2013; 188-193
    PubMedSuche in Google Scholar
  • 59 Kim J, Parrish AB, Kurokawa M et al. Rsk-mediated phosphorylation and 14-3-3ε binding of Apaf-1 suppresses cytochrome c-induced apoptosis. EMBO 2012; 31: 1279-1292
    CrossrefPubMedSuche in Google Scholar
  • 60 Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: Analysis and therapeutic implications. J Pharm Sci 2007; 96: 729-746
    CrossrefPubMedSuche in Google Scholar
  • 61 Eftekhari A, Azarmi Y, Parvizpur A et al. Involvement of oxidative stress and mitochondrial/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes. Xenobiotica 2016; 46: 369-378
    CrossrefPubMedSuche in Google Scholar