PT  - JOURNAL ARTICLE
AU  - Roland F. Staack
AU  - Denis S. Theobald
AU  - Liane D. Paul
AU  - Dietmar Springer
AU  - Thomas Kraemer
AU  - Hans H. Maurer
TI  - IDENTIFICATION OF HUMAN CYTOCHROME P450 2D6 AS MAJOR ENZYME INVOLVED IN THE <em>O</em>-DEMETHYLATION OF THE DESIGNER DRUG <em>P</em>-METHOXYMETHAMPHETAMINE
AID  - 10.1124/dmd.32.4.379
DP  - 2004 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 379--381
VI  - 32
IP  - 4
4099  - http://dmd.aspetjournals.org/content/32/4/379.short
4100  - http://dmd.aspetjournals.org/content/32/4/379.full
SO  - Drug Metab Dispos2004 Apr 01; 32
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics