Investigation of the Susceptibility to Inactivation of 2D6*1 and 2D6*53 by a Known Mechanism-Based Inactivator SCH 66712
Cytochrome P450s (P450s) are a superfamily of heme-containing enzymes that are responsible for the metabolism of many xenobiotics and other small endogenous substrates. CYP2D6 is a major P450 enzyme studied during drug development due to its ability to metabolize ~12-20% of all pharmaceuticals. Moreover, there are over 100 allelic variants of CYP2D6 resulting in a wide-range of drug responses among individuals including cases of adverse drug events. The inactivation of one allelic variant, 2D6*53, by a known-mechanism based inactivator, SCH 66712, was investigated in a time- and concentration-dependent manner alongside the reference *1. Though *1 was inactivated by SCH 66712, *53 was not susceptible to inactivation. The greatly decreased rate of inactivation of *53 suggests that inactivation may be dependent on time and positioning of inactivator in the active site. A trapping assay to capture any SCH 66712 reactive intermediates with NAC and GSH was performed, however, the results were inconclusive as analyzed by mass spectrometry.
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Investigation of CYP 2D6 Variants and their Susceptibility to Inactivation by the Known Mechanism-based Inactivator SCH66712 Osorio, Victoria M. (Kalamazoo College, 2015)Cytochrome P450s (CYPs) are a super family of heme-containing enzymes that in humans metabolize a variety of small molecules including drugs. Human CYP2D6 is responsible for the metabolism of ~12% of all pharmaceutical ...
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