Investigation of CYP 2D6 Variants and their Susceptibility to Inactivation by the Known Mechanism-based Inactivator SCH66712
Osorio, Victoria M.
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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 drugs and has the highest number of functional polymorphic forms among human P450s, causing a variety of phenotypic activity effects. Loss of activity can lead to adverse drug effects and drug-drug interactions. Differences in susceptibility to inactivation are also possible among the variants. SCH 66712 has been previously identified as a mechanism based inactivator of CYP2D6*1. The present study examined the susceptibility to inactivation by SCH 66712 of three CYP2D6 allelic variants with a series of distal mutations (*34, *17-2, *17-3) and one possible ultra-metabolizer (*53). An active site mutant of CYP2D6, T309A, was also studied. Metabolite assays using mass spectrometry determined that all of the variants and the modified 2D6*1 T309A were active and formed the same metabolites. Activity and inactivation assays were performed utilizing bufuralol as a reporter substrate in HPLC coupled UV detection analysis. Although variants showed overall decreased stability in activity assays, in inactivation assays all were less susceptible to inactivation by SCH 66712 when compared to the reference, CYP2D6*1. The study also supports the designation of *53 as an ultra-metabolizer as it produced nearly double the product in activity assays compared to *1 even in the presence of SCH 66712.
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