PMID- 18553070
OWN - NLM
STAT- MEDLINE
DCOM- 20090304
LR  - 20131121
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 83
IP  - 1
DP  - 2009 Jan
TI  - Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its 
      analogues, on isolated rat hepatocytes.
PG  - 69-80
LID - 10.1007/s00204-008-0323-9 [doi]
AB  - 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.
FAU - Nakagawa, Yoshio
AU  - Nakagawa Y
AD  - Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1, 
      Hyakunin-cho, Shinjuku-ku, Tokyo 169-0073, Japan. 
      yoshio_1_nakagawa@member.metro.tokyo.jp
FAU - Suzuki, Toshinari
AU  - Suzuki T
FAU - Tayama, Sumiko
AU  - Tayama S
FAU - Ishii, Hidemi
AU  - Ishii H
FAU - Ogata, Akio
AU  - Ogata A
LA  - eng
PT  - Journal Article
DEP - 20080613
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (Hallucinogens)
RN  - 103818-46-8 (N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine)
RN  - 107447-03-0 (1-(3,4-methylenedioxyphenyl)-2-butanamine)
RN  - 44RAL3456C (Methamphetamine)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - L4I4B1R01F (methylone)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/administration & dosage/analogs & 
      derivatives/toxicity
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Cell Death/drug effects
MH  - DNA Damage/drug effects
MH  - Hallucinogens/administration & dosage/toxicity
MH  - Hepatocytes/*drug effects/metabolism
MH  - Male
MH  - Methamphetamine/administration & dosage/analogs & derivatives/toxicity
MH  - Mitochondria, Liver/*drug effects/metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage/*toxicity
MH  - Oxidative Phosphorylation/drug effects
MH  - Rats
MH  - Rats, Inbred F344
MH  - Time Factors
EDAT- 2008/06/17 09:00
MHDA- 2009/03/05 09:00
CRDT- 2008/06/17 09:00
PHST- 2007/12/13 00:00 [received]
PHST- 2008/05/21 00:00 [accepted]
PHST- 2008/06/17 09:00 [pubmed]
PHST- 2009/03/05 09:00 [medline]
PHST- 2008/06/17 09:00 [entrez]
AID - 10.1007/s00204-008-0323-9 [doi]
PST - ppublish
SO  - Arch Toxicol. 2009 Jan;83(1):69-80. doi: 10.1007/s00204-008-0323-9. Epub 2008 Jun 
      13.