Identification of human cytochrome P450 2D6 as major enzyme involved in the O-demethylation of the designer drug p-methoxymethamphetamine.
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 K(m) and V(max) values in baculovirus-infected insect cell microsomes were 4.6 +/- 1.0 microM and 92.0 +/- 3.7 pmol/min/pmol P450, respectively, and 42.0 +/- 4.0 microM and 412.5 +/- 10.8 pmol/min/mg protein in pHLMs. Inhibition studies with 1 microM 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.
Staack
Roland F
RF
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, Building 46, D-66421 Homburg (Saar), Germany.
Theobald
Denis S
DS
Paul
Liane D
LD
Springer
Dietmar
D
Kraemer
Thomas
T
Maurer
Hans H
HH
D000662:Amphetamines / Q000737:chemistry* / Q000378:metabolism*; D001711:Biotransformation / Q000187:drug effects* / Q000502:physiology; D002853:Chromatography, Liquid / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism*; D015198:Designer Drugs / Q000737:chemistry / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure
D000662:Amphetamines; D015198:Designer Drugs; C060169:4-methoxymethamphetamine; D008694:Methamphetamine; D019389:Cytochrome P-450 CYP2D6