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Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes

  • Organ Toxicity and Mechanisms
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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.

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Abbreviations

MDMA:

3,4-Methylenedioxy-N-methamphetamine

MBDB:

N-Methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine

BDB:

3,4-(Methylenedioxyphenyl)-2-butanamine

Methylone:

2-Methylamino-1-(3,4-methylenedioxyphenyl)propane-1-one

DMSO:

Dimethyl sulfoxide

GSH:

Glutathione reduced form

GSSG:

Glutathione oxidized form

MPT:

Mitochondrial permeability transition

ROS:

Reactive oxygen species

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Acknowledgments

The authors thank Dr. Ichirou Yasuda and his colleagues for providing MDMA and its analogues.

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Authors and Affiliations

  1. Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, Tokyo, 169-0073, Japan

    Yoshio Nakagawa, Toshinari Suzuki, Sumiko Tayama & Akio Ogata

  2. Department of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, 3-3165, Higashitamagawa Gakuen, Machida, Tokyo, 194-0023, Japan

    Hidemi Ishii

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  1. Yoshio Nakagawa
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  2. Toshinari Suzuki
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Correspondence to Yoshio Nakagawa.

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Nakagawa, Y., Suzuki, T., Tayama, S. et al. Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes. Arch Toxicol 83, 69–80 (2009). https://doi.org/10.1007/s00204-008-0323-9

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