3,4-Methylenedioxymethamphetamine ("Ecstasy") induces apoptosis of cultured rat liver cells.
"Ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) has been shown to be hepatotoxic for human users, but molecular mechanisms involved in this effect remained poorly understood. MDMA-induced cell damage is related to programmed cell death in serotonergic and dopaminergic neurons. However, until now there has been no evidence of apoptosis induced by MDMA in liver cells. Here we demonstrate that exposure to MDMA caused apoptosis of freshly isolated rat hepatocytes and of a cell line of hepatic stellate cells (HSC), as shown by chromatin condensation of the nuclei and accumulation of oligonucleosomal fragments in the cytoplasm. In both cell types, apoptosis correlated with decreased levels of bcl-x(L), release of cytochrome c from the mitochondria and activation of caspase 3. In HSC, but not in hepatocytes, MDMA induced poly(ADP-ribose)polymerase (PARP) proteolysis. These results suggest that apoptosis of liver cells could be involved in the hepatotoxicity of MDMA.
Montiel-Duarte
Cristina
C
Department of Biochemistry, University of Navarra, Navarra, Pamplona, Spain.
Varela-Rey
Marta
M
Osés-Prieto
Juan A
JA
López-Zabalza
María Jesús
MJ
Beitia
Guadalupe
G
Cenarruzabeitia
Edurne
E
Iraburu
María J
MJ
D000818:Animals; D017209:Apoptosis; D001562:Benzimidazoles; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry; D003574:Cytochrome c Group / Q000032:analysis; D003593:Cytoplasm / Q000187:drug effects; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology* / Q000633:toxicity; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D001562:Benzimidazoles; D002843:Chromatin; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C017807:bisbenzimide ethoxide trihydrochloride