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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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
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| Series: | Heliyon |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844025013362 |
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| Summary: | 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. |
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| ISSN: | 2405-8440 |