Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity

Abstract

ABSTRACT:Metabolism plays an important role in the toxic effects caused by 3,4-methylenedioxymethamphetamine (MDMA). Most research has focused on the involvement of CYP2D6 enzyme in MDMA bioactivation, and less is known about the contribution of other cytochrome P450 (P450) and phase II metabolism. In this study, we researched the differential roles of phase I P450 enzymes CYP1A2, CYP3A4, and CYP2D6 and phase II enzymes glutathione S-transferase ( 3,4-Methylenedioxymethamphetamine [(MDMA) "ecstasy"] is an illicit drug of abuse that possesses stimulant and hallucinogenic properties. Chemically, it is a ring-substituted phenylamine derivate that became widely available in Europe at the beginning of the 1990s. The use of MDMA is mainly associated with nightclubs, dance music, and some subcultures, and a significantly higher level of use is being reported among young people (EMCDDA, 2008).Consumption of MDMA can lead to severe acute clinical effects such as tachycardia, hypertension, hyperthermia, intracranial hemorrhage, serotonin syndrome, and even death. Furthermore, reported chronic effects have been related to disruption of the serotonergic function (Parrott 2001; Garcia-Repetto et al., 2003;Schifano 2004;de la Torre et al., 2004;Carmo et al., 2006). Cases of hepatotoxicity due to MDMA ingestion have also been reported, yet it is probable that many more cases are subclinical and remain undetected. Subacute hepatotoxicity can ultimately lead to severe liver damage after repeated exposure, and MDMA is considered to be a cause of drug-induced liver injury.In MDMA-induced hepatotoxicity, metabolism appears to play an important role and has been the subject of several studies (Tucker et al., 1994;Malpass et al., 1999;de la Torre et al., 2000;Maurer et al., 2000;Segura et al., 2001;Jones et al., 2005;Milhazes et al., 2006;

Development and validation of an LC‐MS/MS method after chiral derivatization for the simultaneous stereoselective determination of methylenedioxy‐methamphetamine (MDMA) and its phase I and II metabolites in human blood plasma

“…Neurotoxic effects to serotonic neurons have been described, but are still controversial discussed in terms of species and dosing [7][8][9]. MDMA metabolism is suspected to be responsible for neurotoxicity presumably through the formation of glutathion adducts [10][11][12][13][14][15][16]. HMMA can be further conjugated by UDP-glucuronyltransferases or by sulfotransferases.…”

In Vitro and In Vivo Characterization of Reactive Intermediates of Corynoline

“…The P450-mediated metabolic activation generally starts with O-demethylenation of those 1,3-benzodioxole-containing compounds leading to ring opening and formation of a catechol metabolite (Hutzler et al, 2006), followed by oxidation to produce electrophilic ortho-quinones (Hutzler et al, 2008). For example, the generation of an ortho-quinone metabolite derived from 3,4-methylenedioxymethamphetamine is reportedly responsible for toxicities induced by 3,4-methylenedioxymethamphetamine (Tucker et al, 1994;Antolino-Lobo et al, 2010). Sitaxentan, a selective endothelin-A receptor antagonist, was withdrawn from the global market by Pfizer in December 2010 due to its idiosyncratic hepatotoxicity.…”

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

“…MDMA metabolism may be responsible for neurotoxicity, presumably through the formation of glutathione adducts (Hiramatsu et al, 1990;Miller et al, 1997;Bai et al, 1999;Capela et al, 2009;Mueller et al, 2009;Antolino-Lobo et al, 2010;Carvalho et al, 2012), interaction with dopamine and/or serotonin metabolism, and formation of reactive oxygen species (Carvalho et al, 2012). MDMA metabolites were also discussed to play a role in acute cardiovascular effects observed after MDMA consumption (Schindler et al, 2014).…”