PT  - JOURNAL ARTICLE
AU  - Sarah M. Glass
AU  - Cydney M. Martell
AU  - Alexandria K. Oswalt
AU  - Victoria Osorio-Vasquez
AU  - Christi Cho
AU  - Michael J. Hicks
AU  - Jacqueline M. Mills
AU  - Rina Fujiwara
AU  - Michael J. Glista
AU  - Sharat S. Kamath
AU  - Laura Lowe Furge
TI  - CYP2D6 Allelic Variants *34, *17-2, *17-3, and *53 and a Thr309Ala Mutant Display Altered Kinetics and NADPH Coupling in Metabolism of Bufuralol and Dextromethorphan and Altered Susceptibility to Inactivation by SCH 66712
AID  - 10.1124/dmd.117.079871
DP  - 2018 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 1106--1117
VI  - 46
IP  - 8
4099  - http://dmd.aspetjournals.org/content/46/8/1106.short
4100  - http://dmd.aspetjournals.org/content/46/8/1106.full
SO  - Drug Metab Dispos2018 Aug 01; 46
AB  - Metabolic phenotype can be affected by multiple factors, including allelic variation and interactions with inhibitors. Human CYP2D6 is responsible for approximately 20% of cytochrome P450–mediated drug metabolism but consists of more than 100 known variants; several variants are commonly found in the population, whereas others are quite rare. Four CYP2D6 allelic variants—three with a series of mutations distal to the active site (*34, *17-2, *17-3) and one ultra-metabolizer with mutations near the active site (*53), along with reference *1 and an active site mutant of *1 (Thr309Ala)—were expressed, purified, and studied for interactions with the typical substrates dextromethorphan and bufuralol and the inactivator SCH 66712. We found that *34, *17-2, and *17-3 displayed reduced enzyme activity and NADPH coupling while producing the same metabolites as *1, suggesting a possible role for Arg296 in NADPH coupling. A higher-activity variant, *53, displayed similar NADPH coupling to *1 but was less susceptible to inactivation by SCH 66712. The Thr309Ala mutant showed similar activity to that of *1 but with greatly reduced NADPH coupling. Overall, these results suggest that kinetic and metabolic analysis of individual CYP2D6 variants is required to understand their possible contributions to variable drug response and the complexity of personalized medicine.