Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes.
Yoshio Nakagawa, Toshinari Suzuki, Sumiko Tayama, Hidemi Ishii, Akio Ogata
Archives of Toxicology January 2009 DOI: 10.1007/s00204-008-0323-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Freshly isolated rat hepatocytes and isolated rat liver mitochondria |
| Interventions | MDMA MBDB BDB methylone |
| Dose | 0-4.0 mM (MBDB concentration range); MBDB 2 and 4 mM (DNA damage and ROS experiments) |
| Duration | 0-2 h (MBDB time course) |
| Topics | MDMA |
| Key points | MBDB and BDB were more cytotoxic than MDMA and methylone in rat hepatocytes, with MBDB causing concentration- and time-dependent cell death, ATP and glutathione depletion, DNA damage, and reactive oxygen species. The authors propose that cytotoxicity is linked to mitochondrial failure via the mitochondrial permeability transition, uncoupling of oxidative phosphorylation, and ATP depletion, and that nuclei as well as mitochondria are target sites. |
Abstract
The amphetamine-derived designer drugs have been illegally used worldwide as recreational drugs, some of which are known to be hepatotoxic in humans. To compare their cytotoxic effects, 3,4-methylenedioxy-N-methamphetamine (MDMA) and its related analogues, N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4-(methylenedioxyphenyl)-2-butanamine (BDB) and 2-methylamino-1-(3,4-methylenedioxyphenyl)-propane-1-one (methylone) were studied in freshly isolated rat hepatocytes. MBDB caused not only concentration (0-4.0 mM)- and time (0-2 h)-dependent cell death accompanied by the formation of cell blebs, and the loss of cellular ATP and adenine nucleotide pools, and reduced glutathione levels, but also the accumulation of oxidized glutathione. Of the other analogues examined, the cytotoxicity of MBDB and BDB was greater than that of MDMA and methylone, suggesting that hepatotoxicity is generally induced by these drugs. In addition, DNA damage and the induction of reactive oxygen species were greater after the incubation of hepatocytes with MBDB (2 and 4 mM) than after that with MDMA. In isolated liver mitochondria, MBDB/BDB resulted in a greater increase in the rate of state 4 oxygen consumption than did MDMA/methylone, indicating an uncoupling effect and a decrease in the rate of state 3 oxygen consumption in a concentration dependent manner. Furthermore, MBDB resulted in mitochondrial swelling dependent on the mitochondrial permeability transition (MPT); the effect of MDMA was less than that of MBDB. Taken collectively, these results suggest that (1) the onset of cytotoxicity caused by designer drugs such as MBDB and MDMA is linked to mitochondrial failure dependent upon the induction of the MPT accompanied by mitochondrial depolarization and depletion of ATP through uncoupling of oxidative phosphorylation in rat hepatocytes, and (2) MBDB and MDMA elicit DNA damage, suggesting that nuclei as well as mitochondria are target sites of these compounds.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 7
- Metabolism of designer drugs of abuse: an updated review. Current Drug Metabolism June 1, 2010
- Methylone and Monoamine Transporters: Correlation with Toxicity Current Neuropharmacology March 1, 2011
- Synthetic psychoactive cathinones: hypothermia and reduced lethality compared to methamphetamine and methylenedioxymethamphetamine. Pharmacology, Biochemistry, and Behavior April 2020
- Preventive effects of fructose and N-acetyl-L-cysteine against cytotoxicity induced by the psychoactive compounds N-methyl-5-(2-aminopropyl)benzofuran and 3,4-methylenedioxy-N-methamphetamine in isolated rat hepatocytes. Journal of Applied Toxicology February 2018
- Protective effects of physical exercise on MDMA-induced cognitive and mitochondrial impairment. Free radical biology & medicine October 2016
and 2 more in the library
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and 9 more in the library