3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro.
Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT2B) serotonin receptor in mediating the heart valve fibroplasia [valvular heart disease (VHD)] and primary pulmonary hypertension observed in patients taking the now-banned appetite suppressant fenfluramine (Pondimin, Redux). Via large-scale, random screening of a portion of the receptorome, we have discovered that the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its N-demethylated metabolite 3,4-methylenedioxyamphetamine (MDA) each preferentially bind to and activate human recombinant 5-HT2B receptors. We also demonstrate that MDMA and MDA, like fenfluramine and its N-deethylated metabolite norfenfluramine, elicit prolonged mitogenic responses in human valvular interstitial cells via activation of 5-HT2B receptors. We also report that pergolide and dihydroergotamine, two drugs recently demonstrated to induce VHD in humans, potently activate 5-HT2B receptors, thus validating this assay system for its ability to predict medications that might induce VHD. Our discovery that MDMA and a major metabolite, MDA, induce prolonged mitogenic responses in vitro similar to those induced by fenfluramine and norfenfluramine in vivo (i.e., valvular interstitial cell fibroplasia) predict that long-term MDMA use could lead to the development of fenfluramine-like VHD. Because of the widespread abuse of MDMA, these findings have major public health implications. These findings also underscore the necessity of screening current and future drugs at h5-HT2B receptors for agonist actions before their use in humans.
Setola
Vincent
V
Department of Biochemistry, Case Western Reserve University, 2109 Adelbert Road, Cleveland, OH 44106-4935, USA.
Hufeisen
Sandra J
SJ
Grande-Allen
K Jane
KJ
Vesely
Ivan
I
Glennon
Richard A
RA
Blough
Bruce
B
Rothman
Richard B
RB
Roth
Bryan L
BL
D015104:3,4-Methylenedioxyamphetamine / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005277:Fenfluramine / Q000494:pharmacology*; D006349:Heart Valve Diseases / Q000473:pathology; D006801:Humans; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009642:Norfenfluramine / Q000494:pharmacology; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology*
D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D009642:Norfenfluramine; D005277:Fenfluramine; D015104:3,4-Methylenedioxyamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine