Involvement of mitochondrial/lysosomal toxic cross-talk in ecstasy induced liver toxicity under hyperthermic condition.
The initial objectives of this study were to evaluate the extent of 3, 4-methylenedioxymethamphetamine (MDMA) induced loss of cell viability (cytotoxicity), induction of reactive oxygen species formation and damage to sub-cellular organelles (e.g. mitochondria/lysosomes) in freshly isolated rat hepatocytes under normothermic conditions (37 degrees C) and to compare the results with the effects obtained under hyperthermic conditions (41 degrees C). MDMA induced cytotoxicity, reactive oxygen species formation, mitochondrial membrane potential decline and lysosomal membrane leakiness in isolated rat hepatocytes at 37 degrees C. A rise in incubation temperature from 37 degrees C to 41 degrees C had an additive/synergic effect on the oxidative stress markers. We observed variations in mitochondrial membrane potential and lysosomal membrane stability that are significantly (P<0.05) higher than those under normothermic conditions. Antioxidants, reactive oxygen species scavengers, lysosomal inactivators, mitochondrial permeability transition (MPT) pore sealing agents, NADPH P450 reductase inhibitor, and inhibitors of reduced CYP2E1 and CYP2D6 prevented all MDMA induced hepatocyte oxidative stress cytotoxicity markers. It is therefore suggested that metabolic reductive activation of MDMA by reduced cytochrome P450s and glutathione could lead to generation of some biological reactive intermediates which could activate reactive oxygen species generation and cause mitochondrial and lysosomal oxidative stress membrane damages. We finally concluded that hyperthermia could potentiate MDMA induced liver toxicity probably through a mitochondrial/lysosomal toxic cross-talk in freshly isolated rat hepatocytes.
Pourahmad
Jalal
J
Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran. j.pourahmadjaktaji@utoronto.ca
Eskandari
Mohammad Reza
MR
Nosrati
Masoumeh
M
Kobarfard
Farzad
F
Khajeamiri
Ali Reza
AR
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000517:prevention & control; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors; D006213:Hallucinogens / Q000378:metabolism / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects*; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D006213:Hallucinogens; D017382:Reactive Oxygen Species; D005978:Glutathione; D018817:N-Methyl-3,4-methylenedioxyamphetamine