Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and a quinone identified as its glutathione adduct.
M. Hiramatsu, Y. Kumagai, S. Unger, A. Cho
Journal of Pharmacology and Experimental Therapeutics August 1, 1990 DOI: 10.1016/s0022-3565(25)12653-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Rat liver microsomes |
| Intervention | MDMA |
| Measures | high-performance liquid chromatography-electrochemical detection, mass spectral data |
| Topics | MDMA |
| Key points | Rat liver microsomes converted MDMA to N-methyl-alpha-methyldopamine with enantioselectivity, forming significantly more from the (+)-isomer than the (-)-isomer via a cytochrome P-450-dependent reaction. The catecholamine was unstable and rapidly oxidized to a quinone that formed a 1:1 adduct with glutathione and other thiols; this oxidation required NADPH and microsomal protein and was inhibited by superoxide dismutase and reducing agents. The authors suggest this quinone and its thiol adducts may account for some irreversible actions of MDMA on serotonergic neurons. |
Abstract
The in vitro conversion of (+)-3,4-methylenedioxymethamphetamine and (-)-3,4-methylenedioxymethamphetamine to the corresponding catecholamine, 3,4-dihydroxymethamphetamine (N-methyl-alpha-methyldopamine), by rat liver microsomes was examined. Metabolite formation was monitored after short-term incubations using high-performance liquid chromatography-electrochemical detection to determine concentrations of the catecholamine. The formation of N-methyl-alpha-methyldopamine exhibited enantioselectivity and levels were significantly higher after incubation of the (+)-isomer. The reaction appears to be cytochrome P-450 dependent as it was sensitive to SKF 525A and carbon monoxide. The catecholamine was unstable and was metabolized rapidly to a compound capable of forming an adduct with glutathione (GSH) and other thiol compounds. This second oxidation did not appear to be cytochrome P-450-dependent but required NADPH and microsomal protein. Catecholamine oxidation was inhibited by superoxide dismutase and by reducing agents. The same catecholamine oxidation product, characterized as the GSH adduct, could be generated by a xanthine-xanthine oxidase mixture and by tyrosinase. Mass spectral data showed that it was a 1:1 amine GSH adduct. These results indicate that MDMA is oxidized by cytochrome P-450 to the catechol and the catecholamine oxidized by superoxide to a quinone to which GSH or other thiol functions add. The formation of this quinone and its thiol adducts may account for some of the irreversible actions of this compound on serotonergic neurons.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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