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An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis

  • Molecular Toxicology
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Abstract

The liver is a vulnerable target for amphetamine toxicity, but the mechanisms involved in the drug’s hepatotoxicity remain poorly understood. The purpose of the current research was to characterize the mode of death elicited by four amphetamines and to evaluate whether their combination triggered similar mechanisms in immortalized human HepG2 cells. The obtained data revealed a time- and temperature-dependent mortality of HepG2 cells exposed to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy; 1.3 mM), methamphetamine (3 mM), 4-methylthioamphetamine (0.5 mM) and d-amphetamine (1.7 mM), alone or combined (1.6 mM mixture). At physiological temperature (37 °C), 24-h exposures caused HepG2 death preferentially by apoptosis, while a rise to 40.5 °C favoured necrosis. ATP levels remained unaltered when the drugs where tested at normothermia, but incubation at 40.5 °C provoked marked ATP depletion for all treatments. Further investigations on the apoptotic mechanisms triggered by the drugs (alone or combined) showed a decline in BCL-2 and BCL- XL mRNA levels, with concurrent upregulation of BAX, BIM, PUMA and BID genes. Elevation of Bax, cleaved Bid, Puma, Bak and Bim protein levels was also seen. To the best of our knowledge, Puma, Bim and Bak have never been linked with the toxicity induced by amphetamines. Time-dependent caspase-3/-7 activation, but not mitochondrial membrane potential (∆ψm) disruption, also mediated amphetamine-induced apoptosis. The cell dismantling was confirmed by poly(ADP-ribose)polymerase proteolysis. Overall, for all evaluated parameters, no relevant differences were detected between individual amphetamines and the mixture (all tested at equieffective cytotoxic concentrations), suggesting that the mode of action of the amphetamines in combination does not deviate from the mode of action of the drugs individually, when eliciting HepG2 cell death.

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References

  • Andreu V, Mas A, Bruguera M, Salmeron JM, Moreno V, Nogue S, Rodes J (1998) Ecstasy: a common cause of severe acute hepatotoxicity. J Hepatol 29(3):394–397

    Article  PubMed  CAS  Google Scholar 

  • Antolino-Lobo I, Meulenbelt J, van den Berg M, van Duursen MB (2011) A mechanistic insight into 3,4-methylenedioxymethamphetamine (“ecstasy”)-mediated hepatotoxicity. Vet Q 31(4):193–205. doi:10.1080/01652176.2011.642534

    Article  PubMed  Google Scholar 

  • Armenian P, Mamantov TM, Tsutaoka BT, Gerona RR, Silman EF, Wu AH, Olson KR (2012) Multiple MDMA (Ecstasy) overdoses at a rave event: a case series. J Intensive Care Med. doi:10.1177/0885066612445982

    PubMed  Google Scholar 

  • Barros LF, Kanaseki T, Sabirov R, Morishima S, Castro J, Bittner CX, Maeno E, Ando-Akatsuka Y, Okada Y (2003) Apoptotic and necrotic blebs in epithelial cells display similar neck diameters but different kinase dependency. Cell Death Differ 10(6):687–697. doi:10.1038/sj.cdd.4401236

    Article  PubMed  CAS  Google Scholar 

  • Beauvais G, Atwell K, Jayanthi S, Ladenheim B, Cadet JL (2011) Involvement of dopamine receptors in binge methamphetamine-induced activation of endoplasmic reticulum and mitochondrial stress pathways. PLoS ONE 6(12):e28946. doi:10.1371/journal.pone.0028946

    Article  PubMed  CAS  Google Scholar 

  • Beitia G, Cobreros A, Sainz L, Cenarruzabeitia E (1999) 3,4-Methylenedioxymethamphetamine (ecstasy)-induced hepatotoxicity: effect on cytosolic calcium signals in isolated hepatocytes. Liver 19(3):234–241

    Article  PubMed  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Brauer RB, Heidecke CD, Nathrath W, Beckurts KT, Vorwald P, Zilker TR, Schweigart U, Holscher AH, Siewert JR (1997) Liver transplantation for the treatment of fulminant hepatic failure induced by the ingestion of ecstasy. Transpl Int 10(3):229–233

    Article  PubMed  CAS  Google Scholar 

  • Brncic N, Kraus I, Viskovic I, Mijandrusic-Sincic B, Vlahovic-Palcevski V (2006) 3,4-methylenedioxymethamphetamine (MDMA): an important cause of acute hepatitis. Med Sci Monit 12(11):CS107–CS109

    PubMed  Google Scholar 

  • Cadet JL, Ordonez SV, Ordonez JV (1997) Methamphetamine induces apoptosis in immortalized neural cells: protection by the proto-oncogene, bcl-2. Synapse 25(2):176–184. doi:10.1002/(SICI)1098-2396(199702)25:2<176::AID-SYN8>3.0.CO;2-9

    Article  PubMed  CAS  Google Scholar 

  • Capela JP, da Araujo SC, Costa VM, Ruscher K, Fernandes E, Bastos MD, Dirnagl U, Meisel A, Carvalho F (2012) The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons. Neurotoxicology. doi:10.1016/j.neuro.2012.09.005

    PubMed  Google Scholar 

  • Capela JP, Ruscher K, Lautenschlager M, Freyer D, Dirnagl U, Gaio AR, Bastos ML, Meisel A, Carvalho F (2006) Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia. Neuroscience 139(3):1069–1081. doi:10.1016/j.neuroscience.2006.01.007

    Article  PubMed  CAS  Google Scholar 

  • Carvalho F, Remiao F, Soares ME, Catarino R, Queiroz G, Bastos ML (1997) d-Amphetamine-induced hepatotoxicity: possible contribution of catecholamines and hyperthermia to the effect studied in isolated rat hepatocytes. Arch Toxicol 71(7):429–436

    Article  PubMed  CAS  Google Scholar 

  • Carvalho M, Remiao F, Milhazes N, Borges F, Fernandes E, Carvalho F, Bastos ML (2004a) The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine. Toxicology 200(2–3):193–203. doi:10.1016/j.tox.2004.03.016

    Article  PubMed  CAS  Google Scholar 

  • Carvalho M, Remiao F, Milhazes N, Borges F, Fernandes E, Monteiro Mdo C, Goncalves MJ, Seabra V, Amado F, Carvalho F, Bastos ML (2004b) Metabolism is required for the expression of ecstasy-induced cardiotoxicity in vitro. Chem Res Toxicol 17(5):623–632. doi:10.1021/tx049960f

    Article  PubMed  CAS  Google Scholar 

  • Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remiao F, Carvalho F, Bastos ML (2012) Toxicity of amphetamines: an update. Arch Toxicol 86(8):1167–1231. doi:10.1007/s00204-012-0815-5

    Article  PubMed  CAS  Google Scholar 

  • Carvalho M, Carvalho F, Bastos ML (2001) Is hyperthermia the triggering factor for hepatotoxicity induced by 3,4-methylenedioxymethamphetamine (ecstasy)? An in vitro study using freshly isolated mouse hepatocytes. Arch Toxicol 74(12):789–793

    Article  PubMed  CAS  Google Scholar 

  • Carvalho M, Pontes H, Remiao F, Bastos ML, Carvalho F (2010) Mechanisms underlying the hepatotoxic effects of ecstasy. Curr Pharm Biotechnol 11(5):476–495

    Article  PubMed  CAS  Google Scholar 

  • Cerretani D, Bello S, Cantatore S, Fiaschi AI, Montefrancesco G, Neri M, Pomara C, Riezzo I, Fiore C, Bonsignore A, Turillazzi E, Fineschi V (2011) Acute administration of 3,4-methylenedioxymethamphetamine (MDMA) induces oxidative stress, lipoperoxidation and TNFalpha-mediated apoptosis in rat liver. Pharmacol Res 64(5):517–527. doi:10.1016/j.phrs.2011.08.002

    Article  PubMed  CAS  Google Scholar 

  • Coore JR (1996) A fatal trip with ecstasy: a case of 3,4-methylenedioxymethamphetamine/3,4- methylenedioxyamphetamine toxicity. J R Soc Med 89(1):51P–52P

    PubMed  CAS  Google Scholar 

  • Cory S, Huang DC, Adams JM (2003) The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22(53):8590–8607. doi:10.1038/sj.onc.1207102

    Article  PubMed  CAS  Google Scholar 

  • Cunha-Oliveira T, Rego AC, Cardoso SM, Borges F, Swerdlow RH, Macedo T, de Oliveira CR (2006) Mitochondrial dysfunction and caspase activation in rat cortical neurons treated with cocaine or amphetamine. Brain Res 1089(1):44–54. doi:10.1016/j.brainres.2006.03.061

    Article  PubMed  CAS  Google Scholar 

  • De Letter EA, Bouche MP, Van Bocxlaer JF, Lambert WE, Piette MH (2004) Interpretation of a 3,4-methylenedioxymethamphetamine (MDMA) blood level: discussion by means of a distribution study in two fatalities. Forensic Sci Int 141(2–3):85–90. doi:10.1016/j.forsciint.2003.12.015

    Article  PubMed  Google Scholar 

  • De Letter EA, Piette MHA, Lambert WE, Cordonnier JACM (2006) Amphetamines as potential inducers of fatalities: a review in the district of Ghent from 1976–2004. Med Sci Law 46(1):37–65

    Article  PubMed  Google Scholar 

  • De Miglio MR, Muroni MR, Simile MM, Calvisi DF, Tolu P, Deiana L, Carru A, Bonelli G, Feo F, Pascale RM (2000) Implication of Bcl-2 family genes in basal and D-amphetamine-induced apoptosis in preneoplastic and neoplastic rat liver lesions. Hepatology 31(4):956–965. doi:10.1053/he.2000.5411

    Article  PubMed  Google Scholar 

  • Deng X, Cai NS, McCoy MT, Chen W, Trush MA, Cadet JL (2002) Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway. Neuropharmacology 42(6):837–845

    Article  PubMed  CAS  Google Scholar 

  • Deng X, Ladenheim B, Jayanthi S, Cadet JL (2007) Methamphetamine administration causes death of dopaminergic neurons in the mouse olfactory bulb. Biol Psychiatry 61(11):1235–1243. doi:10.1016/j.biopsych.2006.09.010

    Article  PubMed  CAS  Google Scholar 

  • Dias da Silva D, Carmo H, Silva E (2013a) Mixtures of 3,4-methylenedioxymethamphetamine (ecstasy) and its major human metabolites act additively to induce significant toxicity to liver cells even when combined at low, non-cytotoxic concentrations. J Appl Toxicol. doi:10.1002/jat.2885

    Google Scholar 

  • Dias da Silva D, Carmo H, Silva E (2013b) The risky cocktail: what combination effects can we expect between ecstasy and other amphetamines? Arch Toxicol 87(1):111–122. doi:10.1007/s00204-012-0929-9

    Article  PubMed  CAS  Google Scholar 

  • Dias da Silva D, Silva E, Carmo H (2013c) Combination effects of amphetamines under hyperthermia—the role played by oxidative stress. J Appl Toxicol. doi:10.1002/jat.2889

    Google Scholar 

  • Dias da Silva D, Silva E, Carmo H (2013d) Cytotoxic effects of amphetamine mixtures in primary hepatocytes are severely aggravated under hyperthermic conditions. Toxicol In Vitro 27(6):1670–1678. doi:10.1016/j.tiv.2013.04.010

    Article  PubMed  CAS  Google Scholar 

  • Duarte JA, Leao A, Magalhaes J, Ascensao A, Bastos ML, Amado FL, Vilarinho L, Quelhas D, Appell HJ, Carvalho F (2005) Strenuous exercise aggravates MDMA-induced skeletal muscle damage in mice. Toxicology 206(3):349–358. doi:10.1016/j.tox.2004.07.012

    Article  PubMed  CAS  Google Scholar 

  • Dykhuizen RS, Brunt PW, Atkinson P, Simpson JG, Smith CC (1995) Ecstasy induced hepatitis mimicking viral hepatitis. Gut 36(6):939–941

    Article  PubMed  CAS  Google Scholar 

  • Eguchi Y, Shimizu S, Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 57(10):1835–1840

    PubMed  CAS  Google Scholar 

  • Ellis AJ, Wendon JA, Portmann B, Williams R (1996) Acute liver damage and ecstasy ingestion. Gut 38(3):454–458

    Article  PubMed  CAS  Google Scholar 

  • Fineschi V, Centini F, Mazzeo E, Turillazzi E (1999) Adam (MDMA) and Eve (MDEA) misuse: an immunohistochemical study on three fatal cases. Forensic Sci Int 104(1):65–74

    Article  PubMed  CAS  Google Scholar 

  • Garbino J, Henry JA, Mentha G, Romand JA (2001) Ecstasy ingestion and fulminant hepatic failure: liver transplantation to be considered as a last therapeutic option. Vet Hum Toxicol 43(2):99–102

    PubMed  CAS  Google Scholar 

  • Garcia-Repetto R, Moreno E, Soriano T, Jurado C, Gimenez MP, Menendez M (2003) Tissue concentrations of MDMA and its metabolite MDA in three fatal cases of overdose. Forensic Sci Int 135(2):110–114. doi:10.1016/S0379-0738(03)00179-8

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Saez AJ (2012) The secrets of the Bcl-2 family. Cell Death Differ 19(11):1733–1740. doi:10.1038/cdd.2012.105

    Article  PubMed  CAS  Google Scholar 

  • Genc K, Genc S, Kizildag S, Sonmez U, Yilmaz O, Tugyan K, Ergur B, Sonmez A, Buldan Z (2003) Methamphetamine induces oligodendroglial cell death in vitro. Brain Res 982(1):125–130

    Article  PubMed  CAS  Google Scholar 

  • Golstein P, Kroemer G (2007) Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 32(1):37–43. doi:10.1016/j.tibs.2006.11.001

    Article  PubMed  CAS  Google Scholar 

  • Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55(3):463–508

    Article  PubMed  CAS  Google Scholar 

  • Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13(15):1899–1911

    Article  PubMed  CAS  Google Scholar 

  • Henry JA, Jeffreys KJ, Dawling S (1992) Toxicity and deaths from 3,4-methylenedioxymethamphetamine (“ecstasy”). Lancet 340(8816):384–387

    Article  PubMed  CAS  Google Scholar 

  • Ibranyi E, Schonleber J (2003) Acute liver failure caused by Ecstasy. Orv Hetil 144(29):1455–1456

    PubMed  Google Scholar 

  • Jayanthi S, Deng X, Bordelon M, McCoy MT, Cadet JL (2001) Methamphetamine causes differential regulation of pro-death and anti-death Bcl-2 genes in the mouse neocortex. FASEB J 15(10):1745–1752

    Article  PubMed  CAS  Google Scholar 

  • Jayanthi S, Deng X, Noailles PA, Ladenheim B, Cadet JL (2004) Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades. FASEB J 18(2):238–251. doi:10.1096/fj.03-0295com

    Article  PubMed  CAS  Google Scholar 

  • Jimenez A, Jorda EG, Verdaguer E, Pubill D, Sureda FX, Canudas AM, Escubedo E, Camarasa J, Camins A, Pallas M (2004) Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells. Toxicol Appl Pharmacol 196(2):223–234. doi:10.1016/j.taap.2003.12.017

    Article  PubMed  CAS  Google Scholar 

  • Kalant H (2001) The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ 165(7):917–928

    PubMed  CAS  Google Scholar 

  • Kamijo Y, Soma K, Nishida M, Namera A, Ohwada T (2002) Acute liver failure following intravenous methamphetamine. Vet Hum Toxicol 44(4):216–217

    PubMed  Google Scholar 

  • Kanthasamy A, Anantharam V, Ali SF, Kanthasamy AG (2006) Methamphetamine induces autophagy and apoptosis in a mesencephalic dopaminergic neuronal culture model: role of cathepsin-D in methamphetamine-induced apoptotic cell death. Ann N Y Acad Sci 1074:234–244. doi:10.1196/annals.1369.022

    Article  PubMed  CAS  Google Scholar 

  • Kass GE, Eriksson JE, Weis M, Orrenius S, Chow SC (1996) Chromatin condensation during apoptosis requires ATP. Biochem J 318(Pt 3):749–752

    PubMed  CAS  Google Scholar 

  • Kendrick WC, Hull AR, Knochel JP (1977) Rhabdomyolysis and shock after intravenous amphetamine administration. Ann Intern Med 86(4):381–387

    Article  PubMed  CAS  Google Scholar 

  • Khakoo SI, Coles CJ, Armstrong JS, Barry RE (1995) Hepatotoxicity and accelerated fibrosis following 3,4-methylenedioxymetamphetamine (“ecstasy”) usage. J Clin Gastroenterol 20(3):244–247

    Article  PubMed  CAS  Google Scholar 

  • Krasnova IN, Ladenheim B, Cadet JL (2005) Amphetamine induces apoptosis of medium spiny striatal projection neurons via the mitochondria-dependent pathway. FASEB J 19(7):851–853. doi:10.1096/fj.04-2881fje

    PubMed  CAS  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680–685

    Article  PubMed  CAS  Google Scholar 

  • Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185(8):1481–1486

    Article  PubMed  CAS  Google Scholar 

  • Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94(4):491–501

    Article  PubMed  CAS  Google Scholar 

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91(4):479–489

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. doi:10.1006/meth.2001.1262

    Article  PubMed  CAS  Google Scholar 

  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94(4):481–490

    Article  PubMed  CAS  Google Scholar 

  • Ly JD, Grubb DR, Lawen A (2003) The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8(2):115–128

    Article  PubMed  CAS  Google Scholar 

  • Milroy CM (2011) “Ecstasy” associated deaths: what is a fatal concentration ? Analysis of a case series. Forensic Sci Med Pathol 7(3):248–252. doi:10.1007/s12024-010-9220-7

    Article  PubMed  CAS  Google Scholar 

  • Milroy CM, Clark JC, Forrest AR (1996) Pathology of deaths associated with “ecstasy” and “eve” misuse. J Clin Pathol 49(2):149–153

    Article  PubMed  CAS  Google Scholar 

  • Montgomery T, Sitte H, McBean G (2010) 4-Methylthioamphetamine (4-MTA) induces mitochondrial-dependent apoptosis in SH-SY5Y cells independently of dopamine and noradrenaline transporters. BMC Pharmacol 10(Suppl 1):A22

    Article  Google Scholar 

  • Montiel-Duarte C, Ansorena E, Lopez-Zabalza MJ, Cenarruzabeitia E, Iraburu MJ (2004) Role of reactive oxygen species, glutathione and NF-kappaB in apoptosis induced by 3,4-methylenedioxymethamphetamine (“Ecstasy”) on hepatic stellate cells. Biochem Pharmacol 67(6):1025–1033. doi:10.1016/j.bcp.2003.10.020

    Article  PubMed  CAS  Google Scholar 

  • Montiel-Duarte C, Varela-Rey M, Oses-Prieto JA, Lopez-Zabalza MJ, Beitia G, Cenarruzabeitia E, Iraburu MJ (2002) 3,4-Methylenedioxymethamphetamine (“Ecstasy”) induces apoptosis of cultured rat liver cells. Biochim Biophys Acta 1588(1):26–32

    Article  PubMed  CAS  Google Scholar 

  • Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ (2001) Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J Cell Biol 153(6):1265–1276

    Article  PubMed  CAS  Google Scholar 

  • Nicotera P, Leist M, Ferrando-May E (1998) Intracellular ATP, a switch in the decision between apoptosis and necrosis. Toxicol Lett 102–103:139–142

    Article  PubMed  Google Scholar 

  • Ortyn WE, Hall BE, George TC, Frost K, Basiji DA, Perry DJ, Zimmerman CA, Coder D, Morrissey PJ (2006) Sensitivity measurement and compensation in spectral imaging. Cytometry A 69(8):852–862. doi:10.1002/cyto.a.20306

    PubMed  Google Scholar 

  • Patel MM, Belson MG, Longwater AB, Olson KR, Miller MA (2005) Methylenedioxymethamphetamine (ecstasy)-related hyperthermia. J Emerg Med 29(4):451–454. doi:10.1016/j.jemermed.2005.05.007

    Article  PubMed  Google Scholar 

  • Pereira FC, Lourenco ES, Borges F, Morgadinho T, Ribeiro CF, Macedo TR, Ali SF (2006) Single or multiple injections of methamphetamine increased dopamine turnover but did not decrease tyrosine hydroxylase levels or cleave caspase-3 in caudate-putamen. Synapse 60(3):185–193. doi:10.1002/syn.20285

    Article  PubMed  CAS  Google Scholar 

  • Pontes H, Sousa C, Silva R, Fernandes E, Carmo H, Remiao F, Carvalho F, Bastos ML (2008) Synergistic toxicity of ethanol and MDMA towards primary cultured rat hepatocytes. Toxicology 254(1–2):42–50. doi:10.1016/j.tox.2008.09.009

    Article  PubMed  CAS  Google Scholar 

  • Proskuryakov SY, Konoplyannikov AG, Gabai VL (2003) Necrosis: a specific form of programmed cell death? Exp Cell Res 283(1):1–16

    Article  PubMed  CAS  Google Scholar 

  • Rajapakse N, Silva E, Scholze M, Kortenkamp A (2004) Deviation from additivity with estrogenic mixtures containing 4-nonylphenol and 4-tert-octylphenol detected in the E-SCREEN assay. Environ Sci Technol 38(23):6343–6352

    Article  PubMed  CAS  Google Scholar 

  • Richter C, Schweizer M, Cossarizza A, Franceschi C (1996) Control of apoptosis by the cellular ATP level. FEBS Lett 378(2):107–110

    Article  PubMed  CAS  Google Scholar 

  • Sano R, Hasuike T, Nakano M, Kominato Y, Itoh H (2009) A fatal case of myocardial damage due to misuse of the “designer drug” MDMA. Leg Med (Tokyo) 11(6):294–297. doi:10.1016/j.legalmed.2009.09.003

    Article  Google Scholar 

  • Scaduto RC Jr, Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76(1 Pt 1):469–477. doi:10.1016/S0006-3495(99)77214-0

    Article  PubMed  CAS  Google Scholar 

  • Screaton GR, Singer M, Cairns HS, Thrasher A, Sarner M, Cohen SL (1992) Hyperpyrexia and rhabdomyolysis after MDMA (“ecstasy”) abuse. Lancet 339(8794):677–678

    Article  PubMed  CAS  Google Scholar 

  • Shao X, Hu Z, Hu C, Bu Q, Yan G, Deng P, Lv L, Wu D, Deng Y, Zhao J, Zhu R, Li Y, Li H, Xu Y, Yang H, Zhao Y, Cen X (2012) Taurine protects methamphetamine-induced developmental angiogenesis defect through antioxidant mechanism. Toxicol Appl Pharmacol 260(3):260–270. doi:10.1016/j.taap.2012.03.003

    Article  PubMed  CAS  Google Scholar 

  • Silva E, Kabil A, Kortenkamp A (2010) Cross-talk between non-genomic and genomic signalling pathways–distinct effect profiles of environmental estrogens. Toxicol Appl Pharmacol 245(2):160–170. doi:10.1016/j.taap.2010.02.015

    Article  PubMed  CAS  Google Scholar 

  • Simantov R, Tauber M (1997) The abused drug MDMA (Ecstasy) induces programmed death of human serotonergic cells. FASEB J 11(2):141–146

    PubMed  CAS  Google Scholar 

  • Strobbe L, de Jaer CP, Louwerse ES, Rozendaal FW (2007) Fatal ecstasy intoxication in a 22-year-old man. Ned Tijdschr Geneeskd 151(30):1690–1694

    PubMed  CAS  Google Scholar 

  • Stumm G, Schlegel J, Schafer T, Wurz C, Mennel HD, Krieg JC, Vedder H (1999) Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons. FASEB J 13(9):1065–1072

    PubMed  CAS  Google Scholar 

  • Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397(6718):441–446. doi:10.1038/17135

    Article  PubMed  CAS  Google Scholar 

  • Upreti VV, Moon KH, Yu LR, Lee IJ, Eddington ND, Ye X, Veenstra TD, Song BJ (2011) Increased oxidative-modifications of cytosolic proteins in 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-exposed rat liver. Proteomics 11(2):202–211. doi:10.1002/pmic.201000203

    Article  PubMed  CAS  Google Scholar 

  • Vanden Eede H, Montenij LJ, Touw DJ, Norris EM (2012) Rhabdomyolysis in MDMA intoxication: a rapid and underestimated killer “Clean” ecstasy, a safe party drug? J Emerg Med 42(6):655–658. doi:10.1016/j.jemermed.2009.04.057

    Article  PubMed  Google Scholar 

  • Verhagen AM, Vaux DL (2002) Cell death regulation by the mammalian IAP antagonist Diablo/Smac. Apoptosis 7(2):163–166

    Article  PubMed  CAS  Google Scholar 

  • Warren MW, Larner SF, Kobeissy FH, Brezing CA, Jeung JA, Hayes RL, Gold MS, Wang KK (2007) Calpain and caspase proteolytic markers co-localize with rat cortical neurons after exposure to methamphetamine and MDMA. Acta Neuropathol 114(3):277–286. doi:10.1007/s00401-007-0259-9

    Article  PubMed  CAS  Google Scholar 

  • Wirth I, Correns A, Pragst F, Schmeling A (2007) Fatal MDMA-intoxication with postmortem diagnosis of hyperthermia. Arch Kriminol 220(5–6):141–151

    PubMed  Google Scholar 

  • Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA, Korsmeyer SJ (1999) Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400(6747):886–891. doi:10.1038/23730

    Article  PubMed  CAS  Google Scholar 

  • Zamaraeva MV, Sabirov RZ, Maeno E, Ando-Akatsuka Y, Bessonova SV, Okada Y (2005) Cells die with increased cytosolic ATP during apoptosis: a bioluminescence study with intracellular luciferase. Cell Death Differ 12(11):1390–1397. doi:10.1038/sj.cdd.4401661

    Article  PubMed  CAS  Google Scholar 

  • Zhu JP, Xu W, Angulo JA (2005) Disparity in the temporal appearance of methamphetamine-induced apoptosis and depletion of dopamine terminal markers in the striatum of mice. Brain Res 1049(2):171–181. doi:10.1016/j.brainres.2005.04.089

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

4-MTA hydrochloride (racemic mixture) was a kind gift from Dr. David Nichols (Purdue University, West Lafayette, IN). The authors would like to thank Prof. John Sumpter and Dr. Chris Parris (Brunel University, London) for assistance with the flow cytometry. Dr. Sibylle Ermler (University of Brunel, London) is gratefully acknowledged for insightful discussions and useful suggestions. Thanks are also due to Diogo Fernandes (University of Brunel, London) and Maria Riverso (UCL School of Pharmacy, University of London) for technical assistance with Western blotting methodology. This work was supported by the Portuguese Research Council Fundação para a Ciência e para a Tecnologia (FCT) [SFRH/BD/45617/2008 to D.D.S. and Pest-C/EQB/LA0006/2011] and cofounded by the European Community financial support Programa Operacional Factores de Competitividade do Quadro de Referência Estratégico Nacional (QREN POFC).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Faculdade de Medicina, Universidade do Porto, 4200-319, Porto, Portugal

    Diana Dias da Silva

  2. Rede de Química e Tecnologia (REQUIMTE), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313, Porto, Portugal

    Diana Dias da Silva & Helena Carmo

  3. Institute for the Environment, Brunel University, Kingston Lane, Uxbridge, Middlesex, UB8 3PH, UK

    Diana Dias da Silva, Adam Lynch & Elisabete Silva

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  1. Diana Dias da Silva
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  2. Helena Carmo
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  3. Adam Lynch
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  4. Elisabete Silva
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Correspondence to Diana Dias da Silva or Elisabete Silva.

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Dias da Silva, D., Carmo, H., Lynch, A. et al. An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis. Arch Toxicol 87, 2165–2185 (2013). https://doi.org/10.1007/s00204-013-1082-9

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  • DOI: https://doi.org/10.1007/s00204-013-1082-9

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