{"doi":"10.1124/dmd.120.000301","title":"In Vivo Functional Effects of CYP2C9 M1L, a Novel and Common Variant in the Yup’ik Alaska Native Population","abstract":"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 <i>CYP2C9</i> in a cross-section of this population identified <i>CYP2C9 Met1Leu</i> (<i>M1L</i>)<i>,</i> a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. <i>M1L</i> 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 (<i>S</i>)<i>-</i>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 (<i>S</i>)-naproxen <i>O</i>-demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of (<i>S</i>)<i>-</i>naproxen, (<i>S</i>)<i>-O</i>-desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of (<i>S</i>)<i>-O</i>-desmethylnaproxen to unchanged (<i>S</i>)<i>-</i>naproxen in urine was 18.0 ± 8.0 (<i>n</i> = 11) for the homozygous <i>CYP2C9</i><i>Met1</i> reference group and 10.3 ± 6.6 (<i>n</i> = 11) for the <i>Leu1</i> variant carrier group (<i>P</i> = 0.011). The effect of <i>M1L</i> 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. <h3>Significance Statement</h3> The novel <i>CYP2C9 Met1Leu</i> variant in Alaska Native people was recently identified. This study validated (<i>S</i>)<i>-</i>naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the <i>CYP2C9 Leu1</i> variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the <i>CYP2C9 Leu1</i> 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.","journal":"Drug Metabolism and Disposition","year":2021,"id":206516,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":523447,"name":"Scarlett E. Hopkins","orcid":"0000-0001-5641-7751","position":1,"is_corresponding":false},{"id":523448,"name":"Bert B. Boyer","orcid":"0000-0001-5511-4329","position":2,"is_corresponding":false},{"id":24902,"name":"Timothy A. Thornton","orcid":"0000-0001-7071-2642","position":3,"is_corresponding":false},{"id":252366,"name":"Allan E. Rettie","orcid":"0000-0001-9894-8753","position":4,"is_corresponding":false},{"id":331595,"name":"Kenneth E. Thummel","orcid":"0000-0002-7799-3739","position":5,"is_corresponding":false},{"id":790901,"name":"Lindsay M. Henderson","orcid":"0000-0001-9444-4064","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-18T23:51:41.571653Z","pmid":"33632714","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}