PT  - JOURNAL ARTICLE
AU  - Britta Bonn
AU  - Collen M. Masimirembwa
AU  - Neal Castagnoli, Jr.
TI  - Exploration of Catalytic Properties of CYP2D6 and CYP3A4 Through Metabolic Studies of Levorphanol and Levallorphan
AID  - 10.1124/dmd.109.028670
DP  - 2010 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 187--199
VI  - 38
IP  - 1
4099  - http://dmd.aspetjournals.org/content/38/1/187.short
4100  - http://dmd.aspetjournals.org/content/38/1/187.full
SO  - Drug Metab Dispos2010 Jan 01; 38
AB  - CYP2D6 and CYP3A4, two members of the cytochrome P450 superfamily of monooxygenases, mediate the biotransformation of a variety of xenobiotics. The two enzymes differ in substrate specificity and size and characteristics of the active site cavity. The aim of this study was to determine whether the catalytic properties of these isoforms, reflected by the differences observed from crystal structures and homology models, could be confirmed with experimental data. Detailed metabolite identification, reversible inhibition, and time-dependent inhibition were examined for levorphanol and levallorphan with CYP2D6 and CYP3A4. The studies were designed to provide a comparison of the orientations of substrates, the catalytic sites of the two enzymes, and the subsequent outcomes on metabolism and inhibition. The metabolite identification revealed that CYP3A4 catalyzed the formation of a variety of metabolites as a result of presenting different parts of the substrates to the heme. CYP2D6 was a poorer catalyst that led to a more limited number of metabolites that were interpreted in terms to two orientations of the substrates. The inhibition studies showed evidence for strong reversible inhibition of CYP2D6 but not for CYP3A4. Levallorphan acted as a time-dependent inhibitor on CYP3A4, indicating a productive binding mode with this enzyme not observed with CYP2D6 that presumably resulted from close interactions of the N-allyl moiety oriented toward the heme. All the results are in agreement with the large and flexible active site of CYP3A4 and the more restricted active site of CYP2D6. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics