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. Issue 6 (14th May 2013)

• Record Type: Journal Article
• Authors: da, Diana Dias; Silva, Elisabete; Carvalho, Félix; Carmo, Helena
• Is Part Of: Journal of applied toxicology. Volume 34:Issue 6(2014)
• Page Start: 618
• Page End: 627
• Publication Date: 2013-05-14
• Subjects: Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.2885
• Languages: English
• ISSNs: 0260-437X

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Hepatic injury after 3, 4‐methylenedioxymethamphetamine (MDMA; <italic>ecstasy</italic>) intoxications is highly unpredictable and does not seem to correlate with either dosage or frequency of use. The mechanisms involved include the drug metabolic bioactivation and the hyperthermic state of the liver triggered by its thermogenic action and exacerbated by the environmental circumstances of abuse at hot and crowded venues. We became interested in understanding the interaction between <italic>ecstasy</italic> and its metabolites generated <italic>in vivo</italic> as users are always exposed to mixtures of parent drug and metabolites. With this purpose, Hep G2 cells were incubated with MDMA and its main human metabolites methylenedioxyamphetamine (MDA), <italic>α</italic>‐methyldopamine (<italic>α</italic>‐MeDA) and <italic>N</italic>‐methyl‐<italic>α</italic>‐methyldopamine (<italic>N</italic>‐Me‐<italic>α</italic>‐MeDA), individually and in mixture (drugs combined in proportion to their individual EC<sub>01</sub>), at normal (37 °C) and hyperthermic (40.5 °C) conditions. After 48 h, viability was assessed by the 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyl tetrazolium bromide (MTT) assay. Extensive concentration–response analysis was performed with single drugs and the parameters of the individual non‐linear logit fits were used to predict joint effects using the well‐founded models of <italic>concentration addition</italic> (CA) and <italic>independent action</italic> (IA). Experimental testing revealed that mixture effects on cell viability conformed to CA, for both temperature settings. Additionally, substantial combination effects were attained even when each substance was present at concentrations that individually produced unnoticeable effects. Hyperthermic incubations dramatically increased the toxicity of the tested drug and metabolites, both individually and combined. These outcomes suggest that MDMA metabolism has hazard implications to liver cells even when metabolites are found in low concentrations, as they contribute additively to the overall toxic effect of MDMA. Copyright © 2013 John Wiley & Sons, Ltd.</p> </abstract>