IDENTIFICATION OF HUMAN CYTOCHROME P450 2D6 AS MAJOR ENZYME INVOLVED IN THEO-DEMETHYLATION OF THE DESIGNER DRUGP-METHOXYMETHAMPHETAMINE
| Autor: | Dietmar Springer, Liane D Paul, Denis S. Theobald, Thomas Kraemer, Hans H. Maurer, Roland F. Staack |
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| Rok vydání: | 2004 |
| Předmět: |
Quinidine
CYP2D6 Genotype medicine.drug_class Metabolite Pharmaceutical Science Pharmacology Methylation Mass Spectrometry Designer Drugs Methamphetamine chemistry.chemical_compound In vivo medicine Humans Biotransformation Demethylation Molecular Structure biology Amphetamines Cytochrome P450 Designer drug Cytochrome P-450 CYP2D6 chemistry Microsomes Liver Microsome biology.protein Chromatography Liquid medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 32:379-381 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.32.4.379 |
| Popis: | 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%; p0.0001), 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%; p0.0001). According to these studies, CYP2D6 is the major P450 involved in O-demethylation of PMMA. |
| Databáze: | OpenAIRE |
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