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

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, ''ecstasy'') is a popular drug of abuse among young people with stimulant and hallucinogenic properties. The drug is generally thought to be safe among consumers due to its low-mortality rates. However, MDMA-adverse effects can occur and the risks are not clearly associated to a specific pattern since the consumption quantity seems not to be correlated with the initiation and severity of the injury. MDMA-mediated adverse health effects have been widely studied and can be evoked by multiple factors such as hyperthermia, polydrug abuse (drug-drug interactions), the altered release of neurotransmitters, impairment of mitochondrial function and apoptosis, metabolism and immune responses. Another adverse effect often associated with MDMA is liver toxicity, yet the mechanism of MDMA-induced liver toxicity is not completely understood. A critical starting point appears to be the hepatic metabolism of MDMA by phase I and II enzymes, leading to reactive metabolites. Elucidating the mechanism of hepatic injury mediated by MDMA is of high toxicological and clinical relevance. In this review, an overview of the literature and the latest findings with respect to the mechanism of MDMA-mediated liver toxicity is described.

Mixtures of 3,4-methylenedioxymethamphetamine (ecstasy) and its major human metabolites act additively to induce significant toxicity to liver cells when combined at low, non-cytotoxic concentrations

“…Among the putative aspects that may contribute to the described toxicity is MDMA metabolism. In humans, MDMA is principally cleared by hepatic metabolism, which results in production of redox-active metabolites (Antolino-Lobo et al, 2011;Barbosa et al, 2012;Carvalho et al, 2010Carvalho et al, , 2012de la Torre & Farre, 2004). These metabolites formed in vivo may act jointly with the parent compound to produce an overall effect that can be different than that elicited by MDMA alone.…”

Kinetic mechanism of time-dependent inhibition of CYP2D6 by 3,4-methylenedioxymethamphetamine (MDMA): Functional heterogeneity of the enzyme and the reversibility of its inactivation

“…This group also includes 3,4-methylenedioxyamphetamine (MDMA) also known as “ecstasy”. This widespread drug of abuse is metabolized by several cytochrome P450 species, of whose CYP2D6 plays the key role [8], The structure of MDMA and the main routes of its transformation by CYP2D6 are shown in Fig. 1.…”

Mechanisms of hepatocellular toxicity associated with new psychoactive synthetic cathinones

“…Most research concerning stimulant hepatotoxicity has so far focused on 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"). However, the hepatotoxic mechanism of MDMA is currently not entirely understood and multiple factors including polydrug abuse, hyperthermia, and metabolism appear to be associated with liver injury in MDMA users (Antolino-Lobo et al, 2011b;Carvalho et al, 2012;Dias da Silva et al, 2013a;Dias da Silva et al, 2013b). In comparison, data on hepatotoxicity of the newly used synthetic cathinones is currently scarce.…”