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SHORT COMMUNICATION

IDENTIFICATION OF CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF 4'-METHYL--PYRROLIDINOPROPIOPHENONE, A NOVEL SCHEDULED DESIGNER DRUG, IN HUMAN LIVER MICROSOMES

Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, Homburg Saarland, Germany

4'-Methyl--pyrrolidinopropiophenone (MPPP) is a new drug of abuse. It is believed to have an abuse potential similar to that of amphetamines. Previous studies with Wistar rats had shown that MPPP was metabolized mainly by hydroxylation in position 4' followed by dehydrogenation to the corresponding carboxylic acid. The aim of the study presented here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the biotransformation of MPPP to 4'-hydroxymethyl-pyrrolidinopropiophenone. Baculovirus-infected insect cell microsomes and human liver microsomes were used for this purpose. Only CYP2C19 and CYP2D6 catalyzed this hydroxylation. The apparent K_m and V_max values for the latter were 9.8 ± 2.5 µM and 13.6 ± 0.7 pmol/min/pmol P450, respectively. CYP2C19 was not saturable over the tested substrate range (2–1000 µM) and interestingly showed a biphasic kinetic profile with apparent K_m,1 and V_max,1 values of 47.2 ± 12.5 µM and 8.1 ± 1.4 pmol/min/pmol P450, respectively. Experiments with pooled human liver microsomes also revealed biphasic nonsaturable kinetics with apparent K_m,1 and V_max,1 values of 57.0 ± 20.9 µM and 199.7 ± 59.7 pmol/min/mg of protein for the high affinity enzyme, respectively. Incubation of 2 µM MPPP with 3 µM of the CYP2D6-specific inhibitor quinidine resulted in significant (p < 0.01) turnover inhibition (11.8 ± 1.6% of control). Based on kinetic data corrected for the relative activity factors, CYP2D6 is the enzyme mainly responsible for MPPP hydroxylation, confirmed by CYP2D6 inhibition studies.

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