Functional characterization of a common CYP4F11 genetic variant and identification of functionally defective CYP4F11 variants in erythromycin metabolism and 20-HETE synthesis

Yi, Myeongjin; Cho, Sun-Ah; Min, Ji-Young; Kim, Dong Hyun; Shin, Jae‐Gook; Lee, Su-Jun

doi:10.1016/j.abb.2017.03.010

Cited by 13 publications

(13 citation statements)

References 44 publications

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“…The CYP4 family has gained increasing attention for its potential to generate interesting metabolites and dispose of endogenous substrates in recent years. CYP4F11, together with CYP4F2, plays an important role in the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid, and participates in the metabolism of vitamin K 9 . Cyp2a5 , the mouse correlate of human CYP2A6 , encodes an enzyme that exhibited circadian regulation 10 .…”

Section: Determinants Of Pkmentioning

confidence: 99%

Current trends in drug metabolism and pharmacokinetics

Meng

Yang

et al. 2019

Acta Pharmaceutica Sinica B

213

124

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Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug–drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

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Section: Determinants Of Pkmentioning

confidence: 99%

Current trends in drug metabolism and pharmacokinetics

Meng

Yang

et al. 2019

Acta Pharmaceutica Sinica B

213

124

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“…In addition, CYP4A11 exhibited metabolism of the immune suppressant tacrolimus to an inactive form [58]. Although the turnover rates were low compared to those of CYP3A4, CYP4F11 exhibited catalytic activity towards commonly used drugs such as erythromycin, benzphetamine, and chlorpromazine [36,37,59]. CYP4F12 has been reported to slowly metabolize the antihistamine ebastine [60] and the antifungal terfenadine [61].…”

Section: Role Of the Cyp4 Family In The Metabolism Of Drugsmentioning

confidence: 99%

“…In addition, a high intake of polyunsaturated fatty acids was associated with reduced risk of ulcerative colitis in patients with CYP4F3 rs4646904 GG/AG, but not those with the AA genotype [158]. Regarding the CYP4F11 gene, Yi et al found through in vitro methods that CYP4F11 D315N protein showed approximately 50% and 32% decreases in intrinsic clearance of erythromycin and arachidonic acid, respectively, compared to the wild type [37]. The CYP4F11 variant (rs1060463) was associated with small bowel bleeding risk induced by aspirin [159].…”

Section: Genetic Variants Of the Cyp4 Familymentioning

confidence: 99%

Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications

Jarrar

Lee

2019

IJMS

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Enzymes in the cytochrome P450 4 (CYP4) family are involved in the metabolism of fatty acids, xenobiotics, therapeutic drugs, and signaling molecules, including eicosanoids, leukotrienes, and prostanoids. As CYP4 enzymes play a role in the maintenance of fatty acids and fatty-acid-derived bioactive molecules within a normal range, they have been implicated in various biological functions, including inflammation, skin barrier, eye function, cardiovascular health, and cancer. Numerous studies have indicated that genetic variants of CYP4 genes cause inter-individual variations in metabolism and disease susceptibility. Genetic variants of CYP4A11, 4F2 genes are associated with cardiovascular diseases. Mutations of CYP4B1, CYP4Z1, and other CYP4 genes that generate 20-HETE are a potential risk for cancer. CYP4V2 gene variants are associated with ocular disease, while those of CYP4F22 are linked to skin disease and CYP4F3B is associated with the inflammatory response. The present study comprehensively collected research to provide an updated view of the molecular functionality of CYP4 genes and their associations with human diseases. Functional analysis of CYP4 genes with clinical implications is necessary to understand inter-individual variations in disease susceptibility and for the development of alternative treatment strategies.

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“…We isolated each genomic DNA sample from peripheral blood using the QIAamp DNA Blood Kit (Qiagen, Hilden, Germany). Coding regions were amplified with SureSelect (Agilent Technologies, Santa Clara, CA, USA), and paired‐end sequencing of base pairs was performed on an Illumina HiSeq2500 Platform (Illumina Cambridge, Cambridge, UK) as described previously (Yi et al., 2017). We aligned sequence data using a BWA‐MEM algorithm and analyzed it using SureCall 2.1 (Agilent Technologies).…”

Section: Methodsmentioning

confidence: 99%

Identification and functional study of genetic polymorphisms in cyclic nucleotide phosphodiesterase 3A (PDE3A)

Kim

Cho

et al. 2020

Annals of Human Genetics

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Phosphodiesterase 3A (PDE3A) is an enzyme that plays an important role in the regulation of cyclic adenosine monophosphate (cAMP)–mediated intracellular signaling in cardiac myocytes and platelets. PDE3A hydrolyzes cAMP, which results in a decrease in intracellular cAMP levels and leads to platelet activation. Whole‐exome sequencing of 50 DNA samples from a healthy Korean population revealed a total of 13 single nucleotide polymorphisms including five missense variants, D12N, Y497C, H504Q, C707R, and A980V. Recombinant proteins for the five variants of PDE3A (and wild‐type protein) were expressed in a FreeStyle 293 expression system with site‐directed mutagenesis. The expression of the recombinant PDE3A proteins was confirmed with Western blotting. Catalytic activity of the PDE3A missense variants and wild‐type enzyme was measured with a PDE‐based assay. Effects of the missense variants on the inhibition of PDE3A activity by cilostazol were also investigated. All variant proteins showed reduced activity (33–53%; p < .0001) compared to the wild‐type protein. In addition, PDE3A activity was inhibited by cilostazol in a dose‐dependent manner and was further suppressed in the missense variants. Specifically, the PDE3A Y497C showed significantly reduced activity, consistent with the predictions of in silico analyses. The present study provides evidence that individuals carrying the PDE3A Y497C variant may have lower enzyme activity for cAMP hydrolysis, which could cause interindividual variation in cAMP‐mediated physiological functions.

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Functional characterization of a common CYP4F11 genetic variant and identification of functionally defective CYP4F11 variants in erythromycin metabolism and 20-HETE synthesis

Cited by 13 publications

References 44 publications

Current trends in drug metabolism and pharmacokinetics

Current trends in drug metabolism and pharmacokinetics

Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications

Identification and functional study of genetic polymorphisms in cyclic nucleotide phosphodiesterase 3A (PDE3A)

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