In-silico analysis of CYP1A2 (cytochrome P450 1A2) missense mutations: Implications for pharmacogenetics
Cytochrome P450 1A2 (CYP1A2) is a key hepatic enzyme involved in the metabolism of a wide array of drugs and endogenous compounds. Variations in the CYP1A2 gene, specifically single nucleotide polymorphisms (SNPs), can significantly influence its enzymatic activity and individual drug metabolism whi...
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Elsevier
2025-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844025013362 |
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| author | Yasamin Khiabani Nazanin Gholampour-Faroji Habib Rezanejad Mohammad Ehsan Taghavizadeh Yazdi Razieh Farazmand Aliakbar Haddad-Mashadrizeh |
| author_facet | Yasamin Khiabani Nazanin Gholampour-Faroji Habib Rezanejad Mohammad Ehsan Taghavizadeh Yazdi Razieh Farazmand Aliakbar Haddad-Mashadrizeh |
| author_sort | Yasamin Khiabani |
| collection | DOAJ |
| description | Cytochrome P450 1A2 (CYP1A2) is a key hepatic enzyme involved in the metabolism of a wide array of drugs and endogenous compounds. Variations in the CYP1A2 gene, specifically single nucleotide polymorphisms (SNPs), can significantly influence its enzymatic activity and individual drug metabolism which may impact drug efficacy and toxicity. A total of 407 missense mutations were identified across the spectrum of nonsynonymous SNPs in the gene. Positioning the assays facilitated the identification of eight distinct mutant forms of the enzyme corresponding to specific mutations within the active-site cavity of the gene, including R108W, T124I, R137W, A317T, L382W, T385A, L386T, and I386F. Using computational tools, the impact of these SNPs on protein stability and function was examined. Molecular dynamics simulations results revealed several significant structural functional dynamics alterations in variants of CYP1A2, especially in the T385A variant. The molecular docking results for the investigated substrates, including Acetaminophen, Aflatoxin B1, Caffeine, Tacrine, Verapamil, Warfarin, Zileuton, and Clozapine, revealed differential binding affinities for each variant compared to the wild-type. Among these mutant types, variant T385A (rs953378109) was particularly damaging, significantly disrupting the active site of the enzyme, which might affect the metabolism of the warfarin among all tested substrates. Therefore, the disruption could potentially lead to altered drug metabolism in individuals carrying this variant. Understanding the effects of SNPs' on CYP1A2 is crucial for developing personalized medicine and pharmacogenomics approaches, particularly in optimizing drug dosing and predicting adverse drug reactions. |
| format | Article |
| id | doaj-art-99c3dfd4340c4dff815f5ae1f2badca2 |
| institution | DOAJ |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-99c3dfd4340c4dff815f5ae1f2badca22025-08-20T03:01:38ZengElsevierHeliyon2405-84402025-03-01116e4295510.1016/j.heliyon.2025.e42955In-silico analysis of CYP1A2 (cytochrome P450 1A2) missense mutations: Implications for pharmacogeneticsYasamin Khiabani0Nazanin Gholampour-Faroji1Habib Rezanejad2Mohammad Ehsan Taghavizadeh Yazdi3Razieh Farazmand4Aliakbar Haddad-Mashadrizeh5Khayyam Innovation Ecosystem (KIE), Mashhad, Iran; Department of Medical Genetics, National Institute of Genetics and Biotechnology, Tehran, IranIndustrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, IranDepartment of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, IranApplied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, IranKhayyam Innovation Ecosystem (KIE), Mashhad, IranIndustrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran; Corresponding author. Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, 50 Azadi Road, Mashhad, 1401, Iran.Cytochrome P450 1A2 (CYP1A2) is a key hepatic enzyme involved in the metabolism of a wide array of drugs and endogenous compounds. Variations in the CYP1A2 gene, specifically single nucleotide polymorphisms (SNPs), can significantly influence its enzymatic activity and individual drug metabolism which may impact drug efficacy and toxicity. A total of 407 missense mutations were identified across the spectrum of nonsynonymous SNPs in the gene. Positioning the assays facilitated the identification of eight distinct mutant forms of the enzyme corresponding to specific mutations within the active-site cavity of the gene, including R108W, T124I, R137W, A317T, L382W, T385A, L386T, and I386F. Using computational tools, the impact of these SNPs on protein stability and function was examined. Molecular dynamics simulations results revealed several significant structural functional dynamics alterations in variants of CYP1A2, especially in the T385A variant. The molecular docking results for the investigated substrates, including Acetaminophen, Aflatoxin B1, Caffeine, Tacrine, Verapamil, Warfarin, Zileuton, and Clozapine, revealed differential binding affinities for each variant compared to the wild-type. Among these mutant types, variant T385A (rs953378109) was particularly damaging, significantly disrupting the active site of the enzyme, which might affect the metabolism of the warfarin among all tested substrates. Therefore, the disruption could potentially lead to altered drug metabolism in individuals carrying this variant. Understanding the effects of SNPs' on CYP1A2 is crucial for developing personalized medicine and pharmacogenomics approaches, particularly in optimizing drug dosing and predicting adverse drug reactions.http://www.sciencedirect.com/science/article/pii/S2405844025013362CYP1A2Genetic variationnsSNPsDrug administrationActive-site cavitySimulation |
| spellingShingle | Yasamin Khiabani Nazanin Gholampour-Faroji Habib Rezanejad Mohammad Ehsan Taghavizadeh Yazdi Razieh Farazmand Aliakbar Haddad-Mashadrizeh In-silico analysis of CYP1A2 (cytochrome P450 1A2) missense mutations: Implications for pharmacogenetics Heliyon CYP1A2 Genetic variation nsSNPs Drug administration Active-site cavity Simulation |
| title | In-silico analysis of CYP1A2 (cytochrome P450 1A2) missense mutations: Implications for pharmacogenetics |
| title_full | In-silico analysis of CYP1A2 (cytochrome P450 1A2) missense mutations: Implications for pharmacogenetics |
| title_fullStr | In-silico analysis of CYP1A2 (cytochrome P450 1A2) missense mutations: Implications for pharmacogenetics |
| title_full_unstemmed | In-silico analysis of CYP1A2 (cytochrome P450 1A2) missense mutations: Implications for pharmacogenetics |
| title_short | In-silico analysis of CYP1A2 (cytochrome P450 1A2) missense mutations: Implications for pharmacogenetics |
| title_sort | in silico analysis of cyp1a2 cytochrome p450 1a2 missense mutations implications for pharmacogenetics |
| topic | CYP1A2 Genetic variation nsSNPs Drug administration Active-site cavity Simulation |
| url | http://www.sciencedirect.com/science/article/pii/S2405844025013362 |
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