RT Journal Article
SR Electronic
T1 <em>In Vivo</em> Functional Effects of <em>CYP2C9 M1L</em>, a Novel and Common Variant in the Yup'ik Alaska Native Population
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2020-000301
DO 10.1124/dmd.120.000301
A1 Lindsay M. Henderson
A1 Scarlett E. Hopkins
A1 Bert B. Boyer
A1 Timothy A. Thornton
A1 Allan E. Rettie
A1 Kenneth E. Thummel
YR 2021
UL http://dmd.aspetjournals.org/content/early/2021/02/24/dmd.120.000301.abstract
AB Alaska Native people are under-represented in genetic research, but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of CYP2C9 in a cross-section of this population identified CYP2C9M1L (M1L), a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and, thus, can contribute to the risk of an adverse drug response from narrow therapeutic index CYP2C9 substrates, such as (S)-warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of (S)-naproxen O-demethylation by CYP2C9 using activity phenotyped human liver microsomes and selective CYP inhibitors, then developed and validated a novel LC/MS method for simultaneous quantification of (S)-naproxen, (S)-O-desmethyl naproxen, and naproxen acyl glucuronide in human urine. The average ratio of (S)-O-desmethyl naproxen to unchanged (S)-naproxen in urine was 18.0 {plus minus} 8.0 (n = 11) for the homozygous CYP2C9 Met1 reference group and 10.3 {plus minus} 6.6 (n = 11) for the Leu1 variant carrier group (P = 0.011). The effect of M1L variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. Significance Statement Our group recently identified the novel CYP2C9 Met1Leu variant in Alaska Native people. Here, we validated (S)-naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the CYP2C9 Leu1 variant. The results of our pharmacogenetic-pharmacokinetic study suggest that the CYP2C9 Leu1 variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow therapeutic index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.