Abstract
During the past 10 years, the use of methamphetamine (METH) has significantly increased in Iran and around the world. The widespread use of 3,4-methylenedioxymethamphetamine as a recreational drug has been responsible for the incidence of several cases of liver failure in young people. This issue made researchers focus on METH toxicity due to the lack of effective treatment and human health risk assessment. There are several reports showing that its long-term use increases the risk for dopamine depletion, but the toxicity mechanisms of METH in liver are not well understood. Therefore, we aimed to investigate the mitochondrial toxicity mechanisms of METH on isolated mitochondria. Rat liver mitochondria were obtained by differential ultracentrifugation, and the isolated mitochondria were then incubated with different concentrations of METH (2.5–20 μM). Our results showed that this agent could induce oxidative stress via rising in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential collapse, and mitochondrial swelling. In addition, collapse of mitochondrial membrane potential, mitochondrial swelling, and release of cytochrome c following METH treatment were well inhibited by pretreatment of mitochondria with cyclosporin A and butylated hydroxytoluene. Finally, it is suggested that METH could interact with respiratory complexes (II and III) and METH-induced liver toxicity may be the result of its disruptive effect on mitochondrial respiratory chain that is the obvious cause of ROS formation, mitochondrial membrane potential decline, and cytochrome c expulsion which start cell death signaling.
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Abbreviations
- METH:
-
Methamphetamine
- ROS:
-
Reactive oxygen species
- GSH:
-
Reduced glutathione
- DCF-DA:
-
2',7'-dichlorofluorescein diacetate
- TBARs:
-
Thiobarbituric acid reactive substances
- CsA:
-
Cyclosporin A
- MDA:
-
Malondialdehyde
- Rh123:
-
Rhodamine 123
- BSA:
-
Bovine serum albumin
- MPT:
-
Mitochondrial permeability transition
- MMP:
-
Mitochondrial membrane potential
- BHT:
-
Butylated hydroxytoluene
- MTT:
-
3-(4,5-dimethylthiazol-2-yl)-12,5-diphenyltetrazolium bromide
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Acknowledgments
We would like to thank Mrs. Soleimani for providing METH.
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Mashayekhi, V., Eskandari, M.R., Kobarfard, F. et al. Induction of mitochondrial permeability transition (MPT) pore opening and ROS formation as a mechanism for methamphetamine-induced mitochondrial toxicity. Naunyn-Schmiedeberg's Arch Pharmacol 387, 47–58 (2014). https://doi.org/10.1007/s00210-013-0919-3
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DOI: https://doi.org/10.1007/s00210-013-0919-3