Sulfation of the 3,4-methylenedioxymethamphetamine (MDMA) metabolites 3,4-dihydroxymethamphetamine (DHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) and their capability to inhibit human sulfotransferases

Toxicol Lett. 2011 Apr 25;202(2):120-8. doi: 10.1016/j.toxlet.2011.01.026. Epub 2011 Feb 2.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is excreted in human urine mainly as conjugates of its metabolites 3,4-dihydroxymethamphetamine (DHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA). The glucuronidation kinetics of HMMA showed high capacities, but also high K(m) values, unlikely to be reached after recreational user's doses. Therefore, the aim of the present work was to investigate the sulfation of DHMA and HMMA by human sulfotransferases (SULTs) in pooled human liver cytosol (pHLC). The kinetic data showed deviation from typical Michaelis-Menten kinetics. The overall efficiency for HMMA sulfation was calculated to be 2-10 times higher than for glucuronidation. As the sulfation of both MDMA metabolites showed substrate inhibition effects, their inhibitory potential towards typical sulfation reactions in pHLC was tested. The following substrates for typical sulfation reactions were used: nitrophenol, dopamine, estradiol, and dehydroepi androsten dione. Inhibition was observed towards dopamine sulfation by DHMA and HMMA, but not by MDMA. The 1/V vs. 1/S plots indicated a mixed-type or competitive inhibition model for DHMA and HMMA, respectively. In conclusion, the presented data indicated that sulfation of HMMA should be the major conjugation reaction observed in humans. Furthermore, both, DHMA and HMMA, were identified as inhibitors of dopamine sulfation.

MeSH terms

  • Cytosol / drug effects
  • Cytosol / enzymology
  • Cytosol / metabolism
  • Dopamine / metabolism
  • Hallucinogens / metabolism*
  • Hallucinogens / toxicity
  • Humans
  • Kinetics
  • Mandelic Acids / metabolism*
  • Mandelic Acids / toxicity
  • Methamphetamine / analogs & derivatives*
  • Methamphetamine / metabolism
  • Methamphetamine / toxicity
  • N-Methyl-3,4-methylenedioxyamphetamine / metabolism*
  • N-Methyl-3,4-methylenedioxyamphetamine / toxicity
  • Sulfotransferases / antagonists & inhibitors*
  • Sulfotransferases / metabolism

Substances

  • Hallucinogens
  • Mandelic Acids
  • 4-hydroxy-3-methoxymethamphetamine
  • Methamphetamine
  • 3,4-dihydroxymandelic acid
  • Sulfotransferases
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Dopamine