Abstract
p-Methoxymethamphetamine (PMMA) is a new designer drug, listed in many countries as a controlled substance. Several fatalities have been attributed to the abuse of this designer drug. Previous in vivo studies using Wistar rats had shown that PMMA was metabolized mainly by O-demethylation. The aim of the study presented here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the biotransformation of PMMA to p-hydroxymethamphetamine. Baculovirus-infected insect cell microsomes, pooled human liver microsomes (pHLMs), and CYP2D6 poor-metabolizer genotype human liver microsomes (PM HLMs) were used for this purpose. Only CYP2D6 catalyzed O-demethylation. The apparent Km and Vmax values in baculovirus-infected insect cell microsomes were 4.6 ± 1.0 μM and 92.0 ± 3.7 pmol/min/pmol P450, respectively, and 42.0 ± 4.0 μM and 412.5 ± 10.8 pmol/min/mg protein in pHLMs. Inhibition studies with 1 μM quinidine showed significant inhibition of the metabolite formation (67.2 ± 0.6%; p < 0.0001), and comparison of the metabolite formation between pHLMs and PM HLMs revealed significantly lower metabolite formation in the incubations with PM HLMs (87.3 ± 1.1%; p < 0.0001). According to these studies, CYP2D6 is the major P450 involved in O-demethylation of PMMA.
Footnotes
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↵1 Abbreviations used are: PMMA, p-methoxymethamphetamine, International Union of Pure and Applied Chemistry (IUPAC): [1-(4-methoxyphenyl)propane-2-yl](methyl)azane); MDMA, methylenedioxymethamphetamine, IUPAC: [1-(1,3-benzodioxol-5-yl)propane-2-yl](methyl)azane; HO-MA, p-hydroxymethamphetamine, IUPAC: [1-(4-hydroxyphenyl)propane-2-yl](methyl)azane; P450, cytochrome P450; pHLM, pooled human liver microsome; PM HLM, CYP2D6 poor-metabolizer genotype human liver microsome; HO-AM, p-hydroxyamphetamine, IUPAC: 1-(4-hydroxyphenyl)propane-2-ylazane); IS, internal standard; LC-MS, liquid chromatography-mass spectrometry; PM, CYP2D6 poor metabolizer; EM, CYP2D6 extensive metabolizer.
- Received October 30, 2003.
- Accepted January 13, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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IDENTIFICATION OF HUMAN CYTOCHROME P450 2D6 AS MAJOR ENZYME INVOLVED IN THE O-DEMETHYLATION OF THE DESIGNER DRUG P-METHOXYMETHAMPHETAMINE
