Functional Characterization of 21 Rare Allelic CYP1A2 Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin O-Deethylation
| العنوان: | Functional Characterization of 21 Rare Allelic CYP1A2 Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin O-Deethylation |
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| المؤلفون: | Akifumi Oda, Tomoki Nakayoshi, Shuki Yamazaki, Akiko Ueda, Shu Tadaka, Daisuke Saigusa, Eiji Hishinuma, Sakae Saito, Masahiro Hiratsuka, Evelyn Marie Gutiérrez Rico, Masaki Kumondai, Kengo Kinoshita, Yuya Nakanishi, Noriyasu Hirasawa |
| المصدر: | Journal of Personalized Medicine Volume 11 Issue 8 Journal of Personalized Medicine, Vol 11, Iss 690, p 690 (2021) |
| بيانات النشر: | Multidisciplinary Digital Publishing Institute, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Population, Medicine (miscellaneous), Biology, 030226 pharmacology & pharmacy, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Allele, education, Genetics, education.field_of_study, CYP1A2, Phenotype, drug metabolism, 030104 developmental biology, Docking (molecular), Phenacetin, genetic variation, phenacetin, Medicine, cytochrome P450 1A2, Drug metabolism, medicine.drug |
| الوصف: | Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin O-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2075-4426 |
| DOI: | 10.3390/jpm11080690 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ab8ef30ef3083a0bfa9643d1829a32b1 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ab8ef30ef3083a0bfa9643d1829a32b1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20754426 |
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| DOI: | 10.3390/jpm11080690 |