Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and a quinone identified as its glutathione adduct

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 254; no. 2; pp. 521 - 527
• Main Authors: HIRAMATSU, M, KUMAGAI, Y, UNGER, S. E, CHO, A. K
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.08.1990
• Subjects: 3,4-Methylenedioxyamphetamine - analogs & derivatives; 3,4-Methylenedioxyamphetamine - metabolism; Amphetamines - metabolism; Animals; Biological and medical sciences; Cells, Cultured; Chromatography, High Pressure Liquid; Deoxyepinephrine - metabolism; Drug toxicity and drugs side effects treatment; Glutathione - metabolism; Male; Medical sciences; Microsomes, Liver - metabolism; N-Methyl-3,4-methylenedioxyamphetamine; Pharmacology. Drug treatments; Rats; Rats, Inbred Strains; Toxicity: nervous system and muscle; Amphetamine derivatives; Rat; CNS stimulant; Metabolite; Liver; Rodentia; Metabolism toxicity relation; Nervous system; Microsome; In vitro; Serotoninergic neuron; Vertebrata; Mammalia; Serotoninergic pathway; Animal
• ISSN: 0022-3565; 1521-0103

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.