A mechanistic insight into 3,4-methylenedioxymethamphetamine ("ecstasy")-mediated hepatotoxicity

Veterinary Quarterly

Volumn 31, Issue 4, 2011, Pages 193-205

  Antolino Lobo, Irene ^a,b   Meulenbelt, Jan ^a,b,c   van den Berg, Martin ^a   van Duursen, Majorie B M ^a  

^a UTRECHT UNIVERSITY   (Netherlands)

^b NATIONAL INSTITUTE FOR PUBLIC HEALTH AND THE ENVIRONMENT   (Netherlands)

^c UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

CYP3A4; DILI; Ecstasy; GSH; Immunosupression; Liver; MDMA; PPAR; PXR

Indexed keywords

(3 CHLOROPHENYL)PIPERAZINE; 3,4 METHYLENEDIOXYMETHAMPHETAMINE; ACETYLCYSTEINE; AMPHETAMINE; CAFFEINE; CATECHOL METHYLTRANSFERASE; CELL NUCLEUS RECEPTOR; CLOZAPINE; CYTOCHROME P450 3A4; DIAZEPAM; FLUOXETINE; GLUTATHIONE; INTERLEUKIN 8; PAROXETINE; PHENYTOIN; PREGNANE X RECEPTOR; RISPERIDONE; RITONAVIR; TUMOR NECROSIS FACTOR ALPHA;

COCULTURE; CONJUGATION; DEMETHYLATION; DETOXIFICATION; GENETIC POLYMORPHISM; GLUTATHIONE METABOLISM; HUMAN; IC 50; IMMUNE RESPONSE; INTOXICATION; LIVER TOXICITY; METABOLISM; NONHUMAN; OXIDATIVE STRESS; REVIEW; TOXIC HEPATITIS;

3,4-METHYLENEDIOXYAMPHETAMINE; ANIMALS; DRUG-INDUCED LIVER INJURY; HUMANS; IMMUNOSUPPRESSION; LIVER; POLYMORPHISM, GENETIC; STREET DRUGS;

EID: 84856031662     PISSN: 01652176     EISSN: 18755941     Source Type: Journal    
DOI: 10.1080/01652176.2011.642534     Document Type: Review

References (125)

1. Allott K, Redman J. 2007. Are there sex differences associated with the effects of ecstasy/3,4-methylenedioxymethamphetamine (MDMA)? Neurosci Biobehav Rev. 31:327-347.
2. 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. 29:394-397.
3. Antolino-Lobo I, Meulenbelt J, Molendijk J, Nijmeijer SM, Scherpenisse P, van den Berg M, van Duursen MB. 2011. Induction of glutathione synthesis and conjugation by 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dihydroxymethamphetamine (HHMA) in human and rat liver cells, including the protective role of some antioxidants. Toxicology. 289:175-184.
4. Antolino-Lobo I, Meulenbelt J, Nijmeijer SM, Maas-Bakker RF, Meijerman I, van den Berg M, van Duursen MB. 2011. 3,4-Methylenedioxymethamphetamine (MDMA) interacts with therapeutic drugs on CYP3A by inhibition of pregnane X receptor (PXR) activation and catalytic enzyme inhibition. Toxicol Lett. 203:82-91.
5. Antolino-Lobo I, Meulenbelt J, Nijmeijer SM, Scherpenisse P, van den Berg M, van Duursen MB. 2010. Differential roles of phase I and phase II enzymes in 3,4-methylendioxymethamphetamine-induced cytotoxicity. Drug Metab Dispos. 38:1105-1112.
6. Boyle NT, Connor TJ. 2010. Methylenedioxymethamphetamine ('ecstasy')-induced immunosuppression: a cause for concern? Br J Pharmacol. 161:17-32.
7. Camarasa J, Ros C, Pubill D, Escubedo E. 2010. Tumour necrosis factor alpha suppression by MDMA is mediated by peripheral heteromeric nicotinic receptors. Immunopharmacol Immunotoxicol. 32:265-271.
8. Capela JP, Macedo C, Branco PS, Ferreira LM, Lobo AM, Fernandes E, Remiao F, Bastos ML, Dirnagl U, Meisel A, et al. 2007. Neurotoxicity mechanisms of thioether ecstasy metabolites. Neuroscience. 146:1743-1757.
9. Carmo H, Brulport M, Hermes M, Oesch F, Silva R, Ferreira LM, Branco PS, Boer D, Remiao F, Carvalho F, et al. 2006. Influence of CYP2D6 polymorphism on 3,4-methylenedioxymethamphetamine ('ecstasy') cytotoxicity. Pharmacogenet Genom. 16:789-799.
10. Carvalho M, Hawksworth G, Milhazes N, Borges F, Monks TJ, Fernandes E, Carvalho F, Bastos ML. 2002. Role of metabolites in MDMA (ecstasy)-induced nephrotoxicity: an in vitro study using rat and human renal proximal tubular cells. Arch Toxicol. 76:581-588.
11. Carvalho M, Milhazes N, Remiao F, Borges F, Fernandes E, Amado F, Monks TJ, Carvalho F, Bastos ML. 2004. Hepatotoxicity of 3,4-methylenedioxyamphetamine and alpha-methyldopamine in isolated rat hepatocytes: formation of glutathione conjugates. Arch Toxicol. 78:16-24.
12. Carvalho M, Pontes H, Remiao F, Bastos ML, Carvalho F. 2010. Mechanisms underlying the hepatotoxic effects of ecstasy. Curr Pharm Biotechnol. 11:476-495.
13. Carvalho M, Remiao F, Milhazes N, Borges F, Fernandes E, Carvalho F, Bastos ML. 2004. The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine. Toxicology. 200:193-203.
14. Carvalho M, Remiao F, Milhazes N, Borges F, Fernandes E, Monteiro Mdo C, Goncalves MJ, Seabra V, Amado F, Carvalho F, et al. 2004. Metabolism is required for the expression of ecstasy-induced cardiotoxicity in vitro. Chem Res Toxicol. 17:623-632.
15. Chen Y, Johansson E, Yang Y, Miller ML, Shen D, Orlicky DJ, Shertzer HG, Vasiliou V, Nebert DW, Dalton TP. 2010. Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis. J Hepatol. 53: 1085-1094.
16. Cho AK, Hiramatsu M, Distefano EW, Chang AS, Jenden DJ. 1990. Stereochemical differences in the metabolism of 3,4-methylenedioxymethamphetamine in vivo and in vitro: a pharmacokinetic analysis. Drug Metab Dispos. 18:686-691.
17. Cole JC, Sumnall HR. 2003. Altered states: the clinical effects of Ecstasy. Pharmacol Ther. 98:35-58.
18. Connor TJ, Harkin A, Kelly JP. 2005. Methylenedioxymethamphetamine suppresses production of the proinflammatory cytokine tumor necrosis factoralpha independent of a beta-adrenoceptor-mediated increase in interleukin-10. J Pharmacol Exp Ther. 312:134-143.
19. Connor TJ, Kelly JP, McGee M, Leonard BE. 2000. Methylenedioxymethamphetamine (MDMA; ecstasy) suppresses IL-1beta and TNF-alpha secretion following an in vivo lipopolysaccharide challenge. Life Sci. 67:1601-1612.
20. Crisafulli C, Cuzzocrea S. 2009. The role of endogenous and exogenous ligands for the peroxisome proliferator-activated receptor alpha (PPAR-alpha) in the regulation of inflammation in macrophages. Shock. 32:62-73.
21. Das BC, Madhukumar AV, Anguiano J, Kim S, Sinz M, Zvyaga TA, Power EC, Ganellin CR, Mani S. 2008. Synthesis of novel ketoconazole derivatives as inhibitors of the human Pregnane X Receptor (PXR; NR1I2; also termed SXR, PAR). Bioorg Med Chem Lett. 18: 3974-3977.
22. de la Torre R, Farre M, Mathuna BO, Roset PN, Pizarro N, Segura M, Torrens M, Ortuno J, Pujadas M, Cami J. 2005. MDMA (ecstasy) pharmacokinetics in a CYP2D6 poor metaboliser and in nine CYP2D6 extensive metabolisers. Eur J Clin Pharmacol. 61:551-554.
23. de la Torre R, Farre M, Navarro M, Pacifici R, Zuccaro P, Pichini S. 2004. Clinical pharmacokinetics of amphetamine and related substances: monitoring in conventional and non-conventional matrices. Clin Pharmacokinet. 43:157-85.
24. de la Torre R, Farre M, Ortuno J, Mas M, Brenneisen R, Roset PN, Segura J, Cami J. 2000. Non-linear pharmaco-kinetics of MDMA ('ecstasy') in humans. Br J Clin Pharmacol. 49: 104-109.
25. de la Torre R, Farre M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Cami J. 2004. Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit. 26:137-44.
26. Delaforge M, Jaouen M, Bouille G. 1999. Inhibitory metabolite complex formation of methylenedioxymethamphetamine with rat and human cytochrome P450. Particular involvement of CYP 2D. Environ Toxicol Pharmacol. 7:153-158.
27. Delerive P, Fruchart JC, Staels B. 2001. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 169:453-459.
28. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W. 1996. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 384:39-43.
29. Dresser GK, Spence JD, Bailey DG. 2000. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 38:41-57.
30. Easton N, Fry J, O'Shea E, Watkins A, Kingston S, Marsden CA. 2003. Synthesis, in vitro formation, and behavioural effects of glutathione regioisomers of alphamethyldopamine with relevance to MDA and MDMA (ecstasy). Brain Res. 987:144-54.
31. Easton N, Marsden CA. 2006. Ecstasy: are animal data consistent between species and can they translate to humans? J Psychopharmacol. 20:194-210.
32. Editorial team. 2010. The EMCDDA annual report 2010: the state of the drugs problem in Europe. Euro Surveill. 15:19714.
33. Edling Y, Sivertsson LK, Butura A, Ingelman-Sundberg M, Ek M. 2009. Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 23:1387-1395.
34. Ekins S, Chang C, Mani S, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, et al. 2007. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol Pharmacol. 72:592-603.
35. Ellis AJ, Wendon JA, Portmann B, Williams R. 1996. Acute liver damage and ecstasy ingestion. Gut. 38:454-458.
36. Farre M, de la Torre R, Mathuna BO, Roset PN, Peiro AM, Torrens M, Ortuno J, Pujadas M, Cami J. 2004. Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics. Psychopharmacology (Berlin). 173:364-375.
37. Fimognari C, Lenzi M, Hrelia P. 2008. Interaction of the isothiocyanate sulforaphane with drug disposition and metabolism: pharmacological and toxicological implications. Curr Drug Metab. 9:668-678.
38. Friedman H, Newton C, Klein TW. 2003. Microbial infections, immunomodulation, and drugs of abuse. Clin Microbiol Rev. 16:209-219.
39. 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. 135:110-114.
40. Gong H, Singh SV, Singh SP, Mu Y, Lee JH, Saini SPS, Toma D, Ren S, Kagan VE, Day BW, et al. 2006. Orphan nuclear receptor pregnane X receptor sensitizes oxidative stress responses in transgenic mice and cancerous cells. Molecular Endocrinology. 20:279-290.
41. 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. 55:463-508.
42. Griffith OW. 1999. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med. 27:922-935.
43. Griffon B, Cillard J, Chevanne M, Morel I, Cillard P, Sergent O. 2000. Activated macrophages increase the susceptibility of rat hepatocytes to ethanol-induced oxidative stress: conflicting effects of nitric oxide. Alcohol Alcohol. 35:230-235.
44. Gross-Steinmeyer K, Stapleton PL, Tracy JH, Bammler TK, Strom SC, Eaton DL. 2010. Sulforaphaneand phenethyl isothiocyanate-induced inhibition of aflatoxin B1-mediated genotoxicity in human hepatocytes: role of GSTM1 genotype and CYP3A4 gene expression. Toxicol Sci. 116:422-432.
45. Guerrero-Beltran CE, Calderon-Oliver M, MartinezAbundis E, Tapia E, Zarco-Marquez G, Zazueta C, Pedraza-Chaverri J. 2010. Protective effect of sulforaphane against cisplatin-induced mitochondrial alterations and impairment in the activity of NAD(P)H: quinone oxidoreductase 1 and gamma glutamyl cysteine ligase: studies in mitochondria isolated from rat kidney and in LLC-PK1 cells. Toxicol Lett. 199:80-92.
46. Henry JA, Hill IR. 1998. Fatal interaction between ritonavir and MDMA. Lancet. 352:1751-1752.
47. Henry JA, Jeffreys KJ, Dawling S. 1992. Toxicity and deaths from 3,4-methylenedioxymethamphetamine ("ecstasy"). Lancet. 340:384-387.
48. Hewitt NJ, Lecluyse EL, Ferguson SS. 2007. Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, and in vitro-in vivo correlations. Xenobiotica. 37:1196-1224.
49. Heydari A, Yeo KR, Lennard MS, Ellis SW, Tucker GT, Rostami-Hodjegan A. 2004. Mechanism-based inactivation of CYP2D6 by methylenedioxymethamphetamine. Drug Metab Dispos. 32: 1213-1217.
50. Holt MP, Ju C. 2006. Mechanisms of drug-induced liver injury. AAPS J. 8: E48-E54.
51. House RV, Thomas PT, Bhargava HN. 1995. Selective modulation of immune function resulting from in vitro exposure to methylenedioxymethamphetamine (ecstasy). Toxicology. 96:59-69.
52. Huang H, Wang H, Sinz M, Zoeckler M, Staudinger J, Redinbo MR, Teotico DG, Locker J, Kalpana GV, Mani S. 2007. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene. 26:258-268.
53. Huang ZA, Yang H, Chen C, Zeng Z, Lu SC. 2000. Inducers of gamma-glutamylcysteine synthetase and their effects on glutathione synthetase expression. Biochim Biophys Acta. 1493:48-55.
54. Ingelman-Sundberg M. 2005. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics Journal. 5:6-13.
55. Jones AL, Simpson KJ. 1999. Review article: mechanisms and management of hepatotoxicity in ecstasy (MDMA) and amphetamine intoxications. Aliment Pharmacol Ther. 13:129-133.
56. Jones DC, Duvauchelle C, Ikegami A, Olsen CM, Lau SS, de la Torre R, Monks TJ. 2005. Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. J Pharmacol Exp Ther. 313:422-431.
57. Kang KW, Lee SJ, Kim SG. 2005. Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal. 7:1664-1673.
58. Khakoo SI, Coles CJ, Armstrong JS, Barry RE. 1995. Hepatotoxicity and accelerated fibrosis following 3,4-methylenedioxymetamphetamine ("ecstasy") usage. J Clin Gastroenterol. 20:244-247.
59. Kliewer SA, Goodwin B, Willson TM. 2002. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev. 23:687-702.
60. Kohle C, Bock KW. 2009. Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor. Biochem Pharmacol. 77:689-699.
61. Kreth K, Kovar K, Schwab M, Zanger UM. 2000. Identification of the human cytochromes P450 involved in the oxidative metabolism of "Ecstasy"-related designer drugs. Biochem Pharmacol. 59:1563-1571.
62. Lavigne JA, Helzlsouer KJ, Huang H, Strickland PT, Bell DA, Selmin O, Watson MA, Hoffman S, Comstock GW, Yager JD. 1997. An association between the allele coding for a low activity variant of catecholO-methyltransferase and the risk for breast cancer. Cancer Res. 57:5493-5497.
63. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. 1998. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 102:1016-1023.
64. Lemberger T, Staels B, Saladin R, Desvergne B, Auwerx J, Wahli W. 1994. Regulation of the peroxisome proliferator-activated receptor alpha gene by glucocorticoids. J Biol Chem. 269:24527-24530.
65. Li AP. 2009. Evaluation of luciferin-isopropylacetal as a CYP3A4 substrate for human hepatocytes: effects of organic solvents, cytochrome P450 (P450) inhibitors, and P450 inducers. Drug Metab Dispos. 37:1598-1603.
66. Li AP, Kaminski DL, Rasmussen A. 1995. Substrates of human hepatic cytochrome P450 3A4. Toxicology. 104:1-8.
67. Lichti-Kaiser K, Brobst D, Xu C, Staudinger JL. 2009. A systematic analysis of predicted phosphorylation sites within the human pregnane X receptor protein. J Pharmacol Exp Ther. 331:65-76.
68. Lin LY, Di Stefano EW, Schmitz DA, Hsu L, Ellis SW, Lennard MS, Tucker GT, Cho AK. 1997. Oxidation of methamphetamine and methylenedioxymethamphetamine by CYP2D6. Drug Metab Dispos. 25:1059-1064.
69. Lin LY, Kumagai Y, Cho AK. 1992. Enzymatic and chemical demethylenation of (methylenedioxy)amphetamine and (methylenedioxy)methamphetamine by rat brain microsomes. Chem Res Toxicol. 5:401-6.
70. Lu SC. 2009. Regulation of glutathione synthesis. Mol Aspects Med. 30:42-59.
71. Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, Hamilton G, Rizzo C, Jolley S, Gilbert D, et al. 2002. CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos. 30:795-804.
72. Ma B, Prueksaritanont T, Lin JH. 2000. Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 28:125-130.
73. Maheo K, Morel F, Langouet S, Kramer H, Le Ferrec E, Ketterer B, Guillouzo A. 1997. Inhibition of cytochromes P-450 and induction of glutathione-S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res. 57:3649-3652.
74. Malpass A, White JM, Irvine RJ, Somogyi AA, Bochner F. 1999. Acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA) in Sprague-Dawley and Dark Agouti rats. Pharmacol Biochem Behav. 64:29-34.
75. Mas M, Farre M, de la Torre R, Roset PN, Ortuno J, Segura J, Cami J. 1999. Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans. J Pharmacol Exp Ther. 290:136-145.
76. Maurer HH, Bickeboeller-Friedrich J, Kraemer T, Peters FT. 2000. Toxicokinetics and analytical toxicology of amphetamine-derived designer drugs ('Ecstasy'). Toxicol Lett. 112-113:133-142.
77. McWalter GK, Higgins LG, McLellan LI, Henderson CJ, Song L, Thornalley PJ, Itoh K, Yamamoto M, Hayes JD. 2004. Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathioneS-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J Nutr. 134:3499S-3506S.
78. Meyer MR, Peters FT, Maurer HH. 2008a. The role of human hepatic cytochrome P450 isozymes in the metabolism of racemic 3,4-methylenedioxy-methamphetamine and its enantiomers. Drug Metab Dispos. 36:2345-2354.
79. Meyer MR, Peters FT, Maurer HH. 2008b. The role of human hepatic cytochrome P450 isozymes in the metabolism of racemic 3,4-methylenedioxy-methamphetamine and its enantiomers. Drug Metab Dispos. 36:2345-2354.
80. Milhazes N, Cunha-Oliveira T, Martins P, Garrido J, Oliveira C, Rego AC, Borges F. 2006. Synthesis and cytotoxic profile of 3,4-methylenedioxymethamphetamine ("ecstasy") and its metabolites on undifferentiated PC12 cells: A putative structure-toxicity relationship. Chem Res Toxicol. 19:1294-1304.
81. Milosevic N, Maier P. 2000. Lead stimulates intercellular signalling between hepatocytes and Kupffer cells. Eur J Pharmacol. 401:317-328.
82. Modestin J, Nussbaumer C, Angst K, Scheidegger P, Hell D. 1997. Use of potentially abusive psychotropic substances in psychiatric inpatients. Eur Arch Psychiatry Clin Neurosci. 247:146-153.
83. Monks TJ, Jones DC, Bai F, Lau SS. 2004. The role of metabolism in 3,4-({thorn})-methylenedioxyamphetamine and 3,4-({thorn})-methylenedioxymethamphetamine (ecstasy) toxicity. Ther Drug Monit. 26:132-136.
84. Monks TJ, Lau SS. 1997. Biological reactivity of polyphenolic-glutathione conjugates. Chem Res Toxicol. 10:1296-1313.
85. Moore LB, Maglich JM, McKee DD, Wisely B, Willson TM, Kliewer SA, Lambert MH, Moore JT. 2002. Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Mol Endocrinol. 16:977-986.
86. Moradi M, Mojtahedzadeh M, Mandegari A, SoltanSharifi MS, Najafi A, Khajavi MR, Hajibabayee M, Ghahremani MH. 2009. The role of glutathioneS-transferase polymorphisms on clinical outcome of ALI/ARDS patient treated with N-acetylcysteine. Respir Med. 103:434-441.
87. Nakata K, Tanaka Y, Nakano T, Adachi T, Tanaka H, Kaminuma T, Ishikawa T. 2006. Nuclear receptor-mediated transcriptional regulation in Phase I, II, and III xenobiotic metabolizing systems. Drug Metab Pharmacokinet. 21:437-457.
88. O'Mathuna B, Farre M, Rostami-Hodjegan A, Yang J, Cuyas E, Torrens M, Pardo R, Abanades S, Maluf S, Tucker GT, et al. 2008. The consequences of 3,4-methylenedioxymethamphetamine induced CYP2D6 inhibition in humans. J Clin Psychopharmacol. 28:523-529.
89. Pacifici R, Pichini S, Zuccaro P, Farre M, Segura M, Ortuno J, Di Carlo S, Bacosi A, Roset PN, Segura J, et al. 2004. Paroxetine inhibits acute effects of 3,4-methylenedioxymethamphetamine on the immune system in humans. J Pharmacol Exp Ther. 309:285-292.
90. Pacifici R, Zuccaro P, Farre M, Pichini S, Di Carlo S, Roset PN, Lopez CH, Ortuno J, Segura J, Cami J, et al. 2000. Immunomodulating activity of MDMA. Ann NY Acad Sci. 914:215-224.
91. Pacifici R, Zuccaro P, Farre M, Pichini S, Di Carlo S, Roset PN, Palmi I, Ortuno J, Menoyo E, Segura J, et al. 2002. Cell-mediated immune response in MDMA users after repeated dose administration: studies in controlled versus noncontrolled settings. Ann NY Acad Sci. 965:421-433.
92. Parrott AC. 2001. Human psychopharmacology of Ecstasy (MDMA): a review of 15 years of empirical research. Hum Psychopharmacol. 16:557-577.
93. Pessayre D, Tinel M, Larrey D, Cobert B, FunckBrentano C, Babany G. 1983. Inactivation of cytochrome P-450 by a troleandomycin metabolite: protective role of glutathione. J Pharmacol Exp Ther. 224:685-691.
94. Peters JM, Rusyn I, Rose ML, Gonzalez FJ, Thurman RG. 2000. Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis. Carcinogenesis. 21:823-826.
95. Pizarro N, de la Torre R, Joglar J, Okumura N, Perfetti X, Lau SS, Monks TJ. 2008. Serotonergic neurotoxic thioether metabolites of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy): synthesis, isolation, and characterization of diastereoisomers. Chem Res Toxicol. 21: 2272-2279.
96. Pizarro N, Ortuno J, Farre M, Hernandez-Lopez C, Pujadas M, Llebaria A, Joglar J, Roset PN, Mas M, Segura J, et al. 2002. Determination of MDMA and its metabolites in blood and urine by gas chromatographymass spectrometry and analysis of enantiomers by capillary electrophoresis. J Anal Toxicol. 26:157-165.
97. Pontes H, Duarte JA, de Pinho PG, Soares ME, Fernandes E, Dinis-Oliveira RJ, Sousa C, Silva R, Carmo H, Casal S, et al. 2008. Chronic exposure to ethanol exacerbates MDMA-induced hyperthermia and exposes liver to severe MDMA-induced toxicity in CD1 mice. Toxicology. 252:64-71.
98. Ramamoorthy Y, Tyndale RF, Sellers EM. 2001. Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates. Pharmacogenetics. 11: 477-487.
99. Ramamoorthy Y, Yu AM, Suh N, Haining RL, Tyndale RF, Sellers EM. 2002. Reduced ({thorn}/)-3, 4-methylenedioxymethamphetamine ("ecstasy") metabometabolite of 3,4-methylenedioxymethamphetamine: lism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro. Biochem Pharmacol. 63: 2111-2119.
100. Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I, Klaunig JE. 2007. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci. 96:2-15.
101. Rose ML, Rivera CA, Bradford BU, Graves LM, Cattley RC, Schoonhoven R, Swenberg JA, Thurman RG. 1999. Kupffer cell oxidant production is central to the mechanism of peroxisome proliferators. Carcinogenesis. 20:27-33.
102. Ryoo S, Won M, Kim DU, Kim L, Han G, Park SK, Mukaida N, Maeng P, Yoo HS, Hoe KL. 2004. PPARalpha activation abolishes LDL-stimulated IL-8 production via AP-1 deactivation in human aortic smooth muscle cells. Biochem Biophys Res Commun. 318: 329-334.
103. Saad B, Dakwar S, Said O, Abu-Hijleh G, Al Battah F, Kmeel A, Aziazeh H. 2006. Evaluation of medicinal plant hepatotoxicity in co-cultures of hepatocytes and monocytes. Evid Based Complement Alternat Med. 3:93-98.
104. Schifano F. 2004. A bitter pill: overview of ecstasy (MDMA, MDA) related fatalities. Psychopharmacology (Berlin). 173:242-248.
105. Schilt T, Koeter MW, de Win MM, Zinkstok JR, van Amelsvoort TA, Schmand B, den Brink W. 2009. The effect of Ecstasy on memory is moderated by a functional polymorphism in the cathechol-O-methyltransferase (COMT) gene. Eur Neuropsychopharmacol. 19:116-124.
106. Schwab M, Seyringer E, Brauer RB, Hellinger A, Griese EU. 1999. Fatal MDMA intoxication. Lancet. 353:593-594.
107. Segura M, Farre M, Pichini S, Peiro AM, Roset PN, Ramirez A, Ortuno J, Pacifici R, Zuccaro P, Segura J, et al. 2005. Contribution of cytochrome P450 2D6 to 3,4-methylenedioxymethamphetamine disposition in humans: use of paroxetine as a metabolic inhibitor probe. Clin Pharmacokinet. 44:649-660.
108. Segura M, Ortuno J, Farre M, McLure JA, Pujadas M, Pizarro N, Llebaria A, Joglar J, Roset PN, Segura J, et al. 2001. 3,4-Dihydroxymethamphetamine (HHMA). A major in vivo 3,4-methylenedioxymethamphetamine (MDMA) metabolite in humans. Chem Res Toxicol. 14:1203-1208.
109. Sevgiler Y, Uner N. 2010. Tissue-specific effects of fenthion on glutathione metabolism modulated by NAC and BSO in Oreochromis niloticus. Drug Chem Toxicol. 33:348-356.
110. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. 1994. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 270:414-423.
111. 0-diphosphate-glucuronosyltransferase 2B15 in the glucuronidation. Chem Pharm Bull. (Tokyo). 57: 472-475.
112. Spina E, de Leon J. 2007. Metabolic drug interactions with newer antipsychotics: a comparative review. Basic Clin Pharmacol Toxicol. 100:4-22.
113. Spina E, Scordo MG, D'Arrigo C. 2003. Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol. 17:517-538.
114. Squires EJ, Sueyoshi T, Negishi M. 2004. Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J Biol Chem. 279:49307-49314.
115. Straus DS, Glass CK. 2007. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 28:551-558.
116. Takeshita A, Taguchi M, Koibuchi N, Ozawa Y. 2002. Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. J Biol Chem. 277:32453-32458.
117. Tucker GT, Lennard MS, Ellis SW, Woods HF, Cho AK, Lin LY, Hiratsuka A, Schmitz DA, Chu TY. 1994. The demethylenation of methylenedioxymethamphetamine ("ecstasy") by debrisoquine hydroxylase (CYP2D6). Biochem Pharmacol. 47:1151-1156.
118. Van LM, Swales J, Hammond C, Wilson C, Hargreaves JA, Rostami-Hodjegan A. 2007. Kinetics of the time-dependent inactivation of CYP2D6 in cryopreserved human hepatocytes by methylenedioxymethamphetamine (MDMA). Eur J Pharm Sci. 31:53-61.
119. Wu D, Otton SV, Inaba T, Kalow W, Sellers EM. 1997. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol. 53:1605-1612.
120. Yang J, Jamei M, Heydari A, Yeo KR, de la Torre R, Farre M, Tucker GT, Rostami-Hodjegan A. 2006. Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA. J Psychopharmacol. 20:842-849.
121. Yessoufou A, Wahli W. 2010. Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels. Swiss Med Wkly. 140:w13071.
122. Yueh MF, Kawahara M, Raucy J. 2005. High volume bioassays to assess CYP3A4-mediated drug interactions: induction and inhibition in a single cell line. Drug Metab Dispos. 33:38-48.
123. Zhang Y, Bachmeier C, Miller DW. 2003. In vitro and in vivo models for assessing drug efflux transporter activity. Adv Drug Deliv Rev. 55:31-51.
124. Zhang Y, Callaway EC. 2002. High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. Biochem J. 364:301-307.
125. Zhou C, Poulton EJ, Grun F, Bammler TK, Blumberg B, Thummel KE, Eaton DL. 2007. The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Mol Pharmacol. 71:220-229.