Comprehensive in vitro and in silico assessments of metabolic capabilities of 24 genomic variants of CYP2C19 using two different substrates

Myung-Eui Seo; Byung-Joo Min; Nayoon Heo; Kye Hwa Lee; Ju Han Kim

doi:10.3389/fphar.2023.1055991

Comprehensive in vitro and in silico assessments of metabolic capabilities of 24 genomic variants of CYP2C19 using two different substrates

Front Pharmacol. 2023 Jan 12:14:1055991. doi: 10.3389/fphar.2023.1055991. eCollection 2023.

Authors

Myung-Eui Seo¹, Byung-Joo Min², Nayoon Heo³, Kye Hwa Lee⁴, Ju Han Kim^{1

5}

Affiliations

¹ Seoul National University Biomedical Informatics (SNUBI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
² National Forensic Service Seoul Institute, Seoul, South Korea.
³ Department of Mathematics, University of California, Los Angeles, Los Angeles, CA, United States.
⁴ Department of Information Medicine, Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea.
⁵ Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, South Korea.

Abstract

Introduction: Most hepatically cleared drugs are metabolized by cytochromes P450 (CYPs), and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide curated clinical references for CYPs to apply individual genome data for optimized drug therapy. However, incorporating novel pharmacogenetic variants into guidelines takes considerable time. Methods: We comprehensively assessed the drug metabolizing capabilities of CYP2C19 variants discovered through population sequencing of two substrates, S-mephenytoin and omeprazole. Results: Based on established functional assays, 75% (18/24) of the variants not yet described in Pharmacogene Variation (PharmVar) had significantly altered drug metabolizing capabilities. Of them, seven variants with inappreciable protein expression were evaluated as protein damaging by all three in silico prediction algorithms, Sorting intolerant from tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Combined annotation dependent depletion (CADD). The five variants with decreased metabolic capability (<50%) of wild type for either substrates were evaluated as protein damaging by all three in silico prediction algorithms, except CADD exact score of NM_000769.4:c.593T>C that was 19.68 (<20.0). In the crystal structure of the five polymorphic proteins, each altered residue of all those proteins was observed to affect the key structures of drug binding specificity. We also identified polymorphic proteins indicating different tendencies of metabolic capability between the two substrates (5/24). Discussion: Therefore, we propose a methodology that combines in silico prediction algorithms and functional assays on polymorphic CYPs with multiple substrates to evaluate the changes in the metabolism of all possible genomic variants in CYP genes. The approach would reinforce existing guidelines and provide information for prescribing appropriate medicines for individual patients.

Keywords: CPIC guidelines; PharmGkB; PharmVar; cytochrome P450 2C19 (CYP2C19); mephenytoin; omeprazole; pharmacogenetics; pharmacogenomics.

Grants and funding

This research was supported by a grant from the Korean Health Technology R&D Project, by the Ministry of Health and Welfare in the South Korea. Funder: Ministry of Health and Welfare in the South Korea Award Number: HI18C2386 Grant Recipient: JK.