N-Methyl-3,4-methylenedioxyamphetamine-induced hepatotoxicity in rats: Oxidative stress after acute and chronic administration

Ninković, Milica; Malicevic, Zivorad; Selaković, Mirjana; Šimić, Ivan; Vasiljevic, Danijela

doi:10.2298/vsp0402125n

Cited by 15 publications

(15 citation statements)

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“…Potential mechanisms include catecholaminergic stimulation or autooxidation of catecholamines (21), mitochondrial dysfunction and leukocyte recruitment and activation (6), and or coronary vasospasm-induced reperfusion ischemia (6, 21). Recent studies have shown that MDMA metabolites play an important role in the toxicity of this drug (12-15). For example, MDMA is metabolized to catechols, which subsequently form orthoquinones.…”

Section: Discussionmentioning

confidence: 99%

“…Studies revealed that MDMA is metabolized to catechols that can undergo redox cycling, with the formation of reactive (and unstable) orthoquinones, generating large quantities of reactive oxygen and nitrogen species (11). The redox active metabolites of MDMA have also been implicated in the toxic effects of MDMA on the heart, kidney and liver (12-15) in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Metabolites of MDMA Induce Oxidative Stress and Contractile Dysfunction in Adult Rat Left Ventricular Myocytes

et al. 2009

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Repeated administration of MDMA (ecstasy) produces eccentric left ventricular (LV) dilation and diastolic dysfunction. While the mechanism(s) underlying this toxicity are unknown; oxidative stress plays an important role. MDMA is metabolized into redox cycling metabolites that produce superoxide. In this study, we demonstrated that metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes. Metabolites of MDMA used in this study included: alpha-methyl dopamine, N-methyl alpha-methyl dopamine and 2,5-bis(glutathion-S-yl)-alpha-MeDA. Dihydroethidium was used to detect drug-induced increases in reactive oxygen species (ROS) production in ventricular myocytes. Contractile function and changes in intracellular calcium transients were measured in paced (1Hz), Fura-2 AM loaded, myocytes using the IonOptix system. Production of ROS in ventricular myocytes treated with MDMA was not different from control. In contrast, all three metabolites of MDMA exhibited time-and concentration-dependent increases in ROS that were prevented by N-acetyl-cysteine (NAC). The metabolites of MDMA, but not MDMA alone, significantly decreased contractility and impaired relaxation in myocytes stimulated at 1Hz. These effects were prevented by NAC. Together, these data suggest that MDMA-induced oxidative stress in the left ventricle can be due, at least in part, to the metabolism of MDMA to redox active metabolites.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolites of MDMA Induce Oxidative Stress and Contractile Dysfunction in Adult Rat Left Ventricular Myocytes

et al. 2009

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“…A previous experimental study that investigated the effects of MDMA on the liver demonstrated that increased concentrations of superoxide dismutase, decreased levels of glutathione and increased lipid peroxidation were evident even after a single dose of MDMA [23]. Dose-dependent increases in lipid peroxidation were also observed.…”

Section: Discussionmentioning

confidence: 83%

Cardiac oxidative stress determination and myocardial morphology after a single ecstasy (MDMA) administration in a rat model

et al. 2008

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Experimental and clinical data indicate that 3,4-methylenedioxy-N-methylamphetamine (MDMA) abuse can produce significant cardiovascular toxicity. A mechanism may be a direct toxic effect of redox active metabolites of MDMA. To evaluate the effect of a single MDMA dose on cellular antioxidant defence system and to investigate the morphology in male albino rats, total glutathione (GSH), oxidised glutathione (GSSG), ascorbic acid (AA), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and malondialdehyde (MDAL) were studied. The effects were evaluated at 3, 6, 16 and 24 h after MDMA administration. Antioxidant enzymes activity was significantly reduced: GPx (-24%) and SOD (-50%) after 3 h and GR (-19%) after 6 h from treatment. AA levels decrease (-37%) after 3 h and (-30%) after 6 h; MDAL level increased (+119%) after 3 h; GSH levels decreased after 3 (31.3%) and 6 h (37.9%) from MDMA treatment. GSSG content was not affected by ecstasy administration. Myocardial contraction band necrosis (CBN) was already visible in rats killed at 6 h. After 16 h, macrophagic monocytes around the necrotic myocardial cells were observed, and within 24 h, this infiltrate became more widespread with an early removal of the necrotic material. Calcium deposits were observed within ventricular cardiomyocytes with intact nuclei and sarcomeres. Single administration of MDMA can significantly alter the cellular antioxidant defence system and produce oxidative stress which may result in lipid peroxidation and disruption of Ca(2 +) homeostasis. The depression in Ca(2+) regulatory mechanism by reactive oxygen species ultimately results in intracellular Ca(2 +) overload, CBN and cell death.

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“…In vivo studies in mice indicate that oxidative stress and high ambient temperature influence hepatotoxicity in mice (Carvalho et al 2004;Johnson et al 2002). MDMA given at higher doses and at high ambient temperature was associated with sings of oxidative stress and liver abnormalities (Carvalho et al 2002), and repeated injections of 10 mg/kg, but not 5 mg/kg, S-(+)-MDMA, produced some hepatic necrosis (Johnson et al 2002), with more pronounced effects in mice fed a vitamin E deficient diet than in mice receiving sufficient amounts of vitamin E. Studies in rats also found a dose dependent increase in signs of oxidative stress in the liver (Ninkovic et al 2004;Rusinyak et al 2004). …”

Section: Hepatotoxicitymentioning

confidence: 95%

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N-Methyl-3,4-methylenedioxyamphetamine-induced hepatotoxicity in rats: Oxidative stress after acute and chronic administration

Abstract: The increased index of lipid peroxidation and the decreased reduced glutathione levels suggested that MDMA application induced the state of oxidative stress in the liver. These changes were much more expressed after the single administration of MDMA.

Cited by 15 publications

References 24 publications

Metabolites of MDMA Induce Oxidative Stress and Contractile Dysfunction in Adult Rat Left Ventricular Myocytes

Metabolites of MDMA Induce Oxidative Stress and Contractile Dysfunction in Adult Rat Left Ventricular Myocytes

Cardiac oxidative stress determination and myocardial morphology after a single ecstasy (MDMA) administration in a rat model

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