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Mechanism‐Based Inhibition of Human Cytochrome P450 2D6 by Schering 66712
Author(s) -
Mocny Catherine S.,
Arthur Evan J.,
Butler Brendan F.,
Diffenderfer Laura E.,
Palamanda Jairam R.,
Guengerich F. Peter,
Nomeir Amin A.,
Furge Laura Lowe
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.512.3
Subject(s) - chemistry , cytochrome p450 , heme , pharmacology , stereochemistry , enzyme , biochemistry , medicine
Schering 66712 (5‐fluoro‐2‐[4‐[(2‐phenyl‐1H‐imidazol5‐yl)methyl]‐1‐piperzainyl]pyrimidine) is a mechanism‐based inactivator of human cytochrome P450 2D6 (P450 2D6) that displays Type I binding with K S of 0.39 ± 0.10 μM. The partition ratio is approximately 300. Inactivation was not prevented by addition of an exogenous nucleophiles including potassium cyanide. Within 15 minutes of incubation with Schering 66712 and NADPH, ~100% of P450 2D6 activity was lost with ~40% loss in ability to binding CO. These findings support inactivation primarily by adduction of protein. ESI‐LC‐MS analysis of whole protein also indicates the presence of a protein adduct. Modeling of Schering 66712 in the active site of P450 2D6 suggests interaction between the phenyl group of Schering 66712 and the heme iron. (Supported by: NIH GM086767‐01 and RGM086767Z, a grant from the Howard Hughes Medical Institute to Kalamazoo College, and the Hutchcroft Fund of Kalamazoo College).