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
Diana Dias Da Silva, Elisabete Silva, Félix Carvalho, Helena Carmo
Journal of Applied Toxicology June 1, 2014 DOI: 10.1002/jat.2885 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro cell study Peer reviewed |
|---|---|
| Population | Hep G2 human hepatoblastoma cell line |
| Interventions | MDMA methylenedioxyamphetamine (MDA) |
| Duration | 48 h incubation |
| Measures | 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay |
| Topics | MDMA |
| Key points | Mixture effects of MDMA and its metabolites on Hep G2 cell viability conformed to the concentration addition model at both 37 degrees C and 40.5 degrees C, and substantial combination effects occurred even when each substance was present at individually ineffective concentrations. Hyperthermic incubation dramatically increased the toxicity of the drug and metabolites, individually and combined, suggesting metabolites contribute additively to MDMA's overall toxic effect on liver cells. |
Abstract
ABSTRACT: Hepatic injury after 3,4‐methylenedioxymethamphetamine (MDMA; ecstasy) 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 ecstasy and its metabolites generated in vivo 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), α‐methyldopamine (α‐MeDA) and N‐methyl‐α‐methyldopamine (N‐Me‐α‐MeDA), individually and in mixture (drugs combined in proportion to their individual EC01), 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 concentration addition (CA) and independent action (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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 4
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- SLC6A4 binding site and acute prosocial effects of (+/-)-3,4-methylendioxymethamphetamine (MDMA) are evolutionarily conserved in Octopus bimaculoides bioRxiv Preprint Server April 16, 2018
- A Conserved Role for Serotonergic Neurotransmission in Mediating Social Behavior in Octopus. Current Biology October 8, 2018
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