Comparative effects of 3,4-methylenedioxymethamphetamine and 4-methylthioamphetamine on rat liver mitochondrial function.
Ecstasy, which is used as a recreational drug, is a common street name for 3, 4-methylenedioxymethamphetamine (MDMA). Another drug of abuse chemically related, though less common than MDMA, is the amphetamine derivative 4-methylthioamphetamine (MTA). MDMA and MTA induce different systemic and organ-specific effects, including neurotoxicity, hyperthermia, nephrotoxicity, cardiotoxicity and hepatotoxicity. Therefore, it is clear that MDMA and MTA are responsible for inducing organ toxicity. The mechanisms underlying MDMA and MTA-induced hepatotoxicity are multifactorial, and therefore not completely understood. Recent findings indicate interference with cellular bioenergetics as an important toxicological feature of ecstasy. However, less is known about the involvement of mitochondria in MTA-induced hepatotoxicity. Thus, we compared the direct influence of MDMA and MTA on rat liver mitochondrial function [mitochondrial permeability transition (MPT), mitochondrial oxidative stress, and mitochondrial bioenergetics]. It was shown that MTA (from 0.025 up to 0.1mM) was more potent than MDMA (from 0.2 up to 0.5mM) in decreasing the sensitivity of rat liver mitochondria to MPT. However, higher concentrations of MTA (from 0.5 up to 2mM) were highly toxic to mitochondria. MTA simultaneously increased H(2)O(2) production in a monoamine oxidase (MAO)-dependent way, and uncoupled and inhibited mitochondrial respiration. In contrast, MDMA had only limited or no effects on these mitochondrial parameters. According to these results, it is possible to postulate that, depending on the concentration, MTA can potentially be more efficient in its effects on liver mitochondria than MDMA and, also, that its harmful effects may contribute to its hepatotoxicity.
Custódio
José B A
JB
CNC, Laboratório de Bioquímica, Faculdade de Farmácia, Universidade de Coimbra, 3000-295 Coimbra, Portugal.
Santos
Maria S
MS
Gonçalves
Dália I R
DI
Moreno
António J M
AJ
Fernandes
Eduarda
E
Bastos
Maria L
ML
Carvalho
Félix
F
Vicente
Joaquim A F
JA
Fernandes
Maria A S
MA
D018759:Adrenergic Uptake Inhibitors / Q000633:toxicity*; D000662:Amphetamines / Q000633:toxicity*; D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D006213:Hallucinogens / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism
D018759:Adrenergic Uptake Inhibitors; D000662:Amphetamines; D006213:Hallucinogens; D013438:Sulfhydryl Compounds; C078956:4-methylthioamphetamine; D006861:Hydrogen Peroxide; D018817:N-Methyl-3,4-methylenedioxyamphetamine