| SOFT - TIAFT 1998 | Poster Session 3 | Thursday October 8, 1998 |
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IN VITRO STUDIES ON THE INFLUENCE OF CYTOCHROME P450 ISOENZYMES ON THE HUMAN OR RAT METABOLISM OF THE DESIGNER DRUGS MDMA AND MDE Joerg Bickeboeller-Friedrich and Hans H. Maurer Institute of Pharmacology and Toxicology, Department of Toxicology, University of Saarland, D-66421 Homburg (Saar), Germany |
| In vitro studies have been described indicating that the demethylenation of MDMA was catalyzed by polymorphic CYP2D6 (Tucker G.T. et al. Biochem. Pharmacol. 47, 1993, 1151). The resulting catechol and/or its oxidation products are claimed to be responsible for the neuro- and/or hepatotoxic effects. However, Colado et al. (Br. J. Pharmacol. 11, 1995, 1281) showed that in CYP2D1/6 deficient rats the catechols of MDMA and MDA could also be formed. The aim of our studies was to elucidate, which metabolic pathway is catalyzed by the main CYP isoforms CYP1A2, CYP2C, CYP2D1/6, and/or CYP3A. In addition, we studied, whether structure analogies could be found and whether differences in humans or rats could be observed. The influence of cytosolic enzymes was also studied. Racemic MDMA and MDE were incubated with human or rat liver microsome and/or cytosol preparations with and without addition of the corresponding cosubstrates and/or specific inhibitors. The metabolites were analyzed by GC-MS (for details cf. Ther. Drug Monit. 18, 1996, 465).
In humans and rats the N-dealkylation of MDMA was predominantly catalyzed by CYP1A2 and CYP2C and of MDE by CYP3A. First, we were not able to demonstrate in microsomes the influence of CYP`s on the demethylenation of MDMA and MDE to the corresponding catechols. To check, whether this effect was due to the instability of the catechols, we incubated the drugs with both, microsomes and cytosol. Thus, the catechols could be stabilized in statu nascendi by COMT methylation. In this way, we were able to show, that CYP2D1/6 and CYP3A were predominantly responsible for the demethylenation of MDE in humans and rats, and of MDMA in rats. Interestingly, we have found that the drugs could also be demethylenated in cytosol in presence of NAD. In conclusion, our data show, that the toxicologically relevant demethylation of designer drugs is catalyzed not only by the polymorphic CYP2D1/6, but also by the non-polymorphic main isoenzyme CYP3A. Therefore, a polymorphism (poor vs. extensive metabolizer) in this presumed toxification step could not be concluded. Enantioselective studies are in progress. |
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