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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
Author(s) -
Nakagawa Yoshio,
Suzuki Toshinari,
Inomata Akiko
Publication year - 2018
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.3523
Subject(s) - mdma , glutathione , pharmacology , chemistry , cytotoxicity , caffeine , oxidative stress , toxicity , fructose , biochemistry , mitochondrion , biology , in vitro , enzyme , endocrinology , organic chemistry
Psychoactive compounds, N ‐methyl‐5‐(2‐aminopropyl)benzofuran (5‐MAPB) and 3,4‐methylenedioxy‐ N ‐methamphetamine (MDMA), are known to be hepatotoxic in humans and/or experimental animals. As previous studies suggested that these compounds elicited cytotoxicity via mitochondrial dysfunction and/or oxidative stress in rat hepatocytes, the protective effects of fructose and N ‐acetyl‐ l ‐cysteine (NAC) on 5‐MAPB‐ and MDMA‐induced toxicity were studied in rat hepatocytes. These drugs caused not only concentration‐dependent (0–4 m m ) and time‐dependent (0–3 hours) cell death accompanied by the depletion of cellular levels of adenosine triphosphate (ATP) and glutathione (reduced form; GSH) but also an increase in the oxidized form of GSH. The toxic effects of 5‐MAPB were greater than those of MDMA. Pretreatment of hepatocytes with either fructose at a concentration of 10 m m or NAC at a concentration of 2.5 m m prevented 5‐MAPB−/MDMA‐induced cytotoxicity. In addition, the exposure of hepatocytes to 5‐MAPB/MDMA caused the loss of mitochondrial membrane potential, although the preventive effect of fructose was weaker than that of NAC. These results suggest that: (1) 5‐MAPB−/MDMA‐induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were ameliorated, at least in part, by the addition of fructose; and (3) GSH loss via oxidative stress was prevented by NAC. Taken collectively, these results indicate that the onset of toxic effects caused by 5‐MAPB/MDMA may be partially attributable to cellular energy stress as well as oxidative stress.