PMID- 24591155
OWN - NLM
STAT- MEDLINE
DCOM- 20141228
LR  - 20211021
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 139
IP  - 1
DP  - 2014 May
TI  - Catechol-o-methyltransferase and 3,4-(+/-)-methylenedioxymethamphetamine 
      toxicity.
PG  - 162-73
LID - 10.1093/toxsci/kfu035 [doi]
AB  - Metabolism of 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) is necessary to elicit 
      its neurotoxic effects. Perturbations in phase I and phase II hepatic enzymes can 
      alter the neurotoxic profile of systemically administered MDMA. In particular, 
      catechol-O-methyltransferase (COMT) plays a critical role in determining the 
      fraction of MDMA that is converted to potentially neurotoxic metabolites. Thus, 
      cytochrome P450 mediated demethylenation of MDMA, or its N-demethylated 
      metabolite, 3,4-(+/-)-methylenedioxyamphetamine, give rise to the catechols, 
      N-methyl-alpha-methyldopamine and alpha-methyldopamine, respectively. Methylation of 
      these catechols by COMT limits their oxidation and conjugation to glutathione, a 
      process that ultimately gives rise to neurotoxic metabolites. We therefore 
      determined the effects of modulating COMT, a critical enzyme involved in 
      determining the fraction of MDMA that is converted to potentially neurotoxic 
      metabolites, on MDMA-induced toxicity. Pharmacological inhibition of COMT in the 
      rat potentiated MDMA-induced serotonin deficits and exacerbated the acute 
      MDMA-induced hyperthermic response. Using a genetic mouse model of COMT 
      deficiency, in which mice lack a functional COMT gene, such mice displayed 
      greater reductions in dopamine concentrations relative to their wild-type (WT) 
      counterparts. Neither WT nor COMT deficient mice were susceptible to MDMA-induced 
      decreases in serotonin concentrations. Interestingly, mice devoid of COMT were 
      far more susceptible to the acute hyperthermic effects of MDMA, exhibiting 
      greater increases in body temperature that ultimately resulted in death. Our 
      findings support the view that COMT plays a pivotal role in determining the toxic 
      response to MDMA.
FAU - Herndon, Joseph M
AU  - Herndon JM
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, Arizona 85721.
FAU - Cholanians, Aram B
AU  - Cholanians AB
FAU - Lizarraga, Lucina E
AU  - Lizarraga LE
FAU - Lau, Serrine S
AU  - Lau SS
FAU - Monks, Terrence J
AU  - Monks TJ
LA  - eng
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - DA023525/DA/NIDA NIH HHS/United States
GR  - T32 ES007091/ES/NIEHS NIH HHS/United States
GR  - 5T32ES007091/ES/NIEHS NIH HHS/United States
GR  - R01 DA023525/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140303
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Benzophenones)
RN  - 0 (DNA Primers)
RN  - 125628-97-9 (Ro 41-0960)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - EC 2.1.1.6 (Catechol O-Methyltransferase)
RN  - X4W3ENH1CV (Norepinephrine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/*toxicity
MH  - Animals
MH  - Base Sequence
MH  - Benzophenones/pharmacology
MH  - Catechol O-Methyltransferase/*metabolism
MH  - Chromatography, High Pressure Liquid
MH  - DNA Primers
MH  - Electrochemical Techniques
MH  - Female
MH  - Fever/chemically induced
MH  - Liver/drug effects/enzymology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Norepinephrine/blood
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC4007109
OTO - NOTNLM
OT  - 3,4-(+/-)-methylenedioxymethamphetamine
OT  - catechol-O-methyltransferase
OT  - hyperthermia
EDAT- 2014/03/05 06:00
MHDA- 2014/12/30 06:00
PMCR- 2015/05/01
CRDT- 2014/03/05 06:00
PHST- 2014/03/05 06:00 [entrez]
PHST- 2014/03/05 06:00 [pubmed]
PHST- 2014/12/30 06:00 [medline]
PHST- 2015/05/01 00:00 [pmc-release]
AID - kfu035 [pii]
AID - 10.1093/toxsci/kfu035 [doi]
PST - ppublish
SO  - Toxicol Sci. 2014 May;139(1):162-73. doi: 10.1093/toxsci/kfu035. Epub 2014 Mar 3.