PT  - JOURNAL ARTICLE
AU  - Marcucci, Kenda A.
AU  - Pearce, Robin E.
AU  - Crespi, Charles
AU  - Steimel, Dorothy T.
AU  - Leeder, J. Steven
AU  - Gaedigk, Andrea
TI  - Characterization of Cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2, and CYP2D6.17 Activities toward Model CYP2D6 Substrates Dextromethorphan, Bufuralol, and Debrisoquine
AID  - 10.1124/dmd.30.5.595
DP  - 2002 May 01
TA  - Drug Metabolism and Disposition
PG  - 595--601
VI  - 30
IP  - 5
4099  - http://dmd.aspetjournals.org/content/30/5/595.short
4100  - http://dmd.aspetjournals.org/content/30/5/595.full
SO  - Drug Metab Dispos2002 May 01; 30
AB  - Over 50 allelic variants of cytochrome P450 2D6 (CYP2D6) encoding fully functional, reduced-activity, or nonfunctional proteins have been described. Compared with Caucasians, studies in black populations demonstrate a tendency toward slower CYP2D6 activity, attributed in part to the presence of a variant allele associated with reduced activity, the CYP2D6*17 allele. To investigate the kinetic characteristics of this variant protein, expression constructs coding for CYP2D6.1, CYP2D6.2, and CYP2D6.17 gene products were prepared and transfected into mammalian COS-7 and insect (Trichoplusia ni) cells for expression. Microsomal fractions containing the expressed proteins were used to determine the kinetic parameters Km,Vmax, and intrinsic clearance (Clint) for the model substrates dextromethorphan, bufuralol, and debrisoquine. Relative to the wild-type CYP2D6.1 protein expressed in COS-7 cells, CYP2D6.17 exhibited a 2-fold higherKm and a 50% reduction inVmax using dextromethorphan as the substrate. In contrast, no appreciable change in bufuralolKm was observed with CYP2D6.17 whereasVmax was decreased by 50%. When expressed in the baculovirus expression system, CYP2D6.17 exhibited a 6-fold increase in Km but no change inVmax with dextromethorphan as the substrate, a 2-fold higher Km and 50% reduction inVmax with bufuralol, and a 3-fold increase in Km and no change inVmax with debrisoquine relative to CYP2D6.1. These data indicate that CYP2D6.17 exhibits reduced metabolic activity toward all three commonly used CYP2D6 substrates, although specific effects on substrate affinity and turnover demonstrate some substrate dependence. The American Society for Pharmacology and Experimental Therapeutics