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1
HENG, Yee M., C. W. Sharon KUO, Paul S. JONES, et al. "A novel murine P-450 gene, Cyp4a14, is part of a cluster of Cyp4a and Cyp4b, but not of CYP4F, genes in mouse and humans." Biochemical Journal 325, no. 3 (1997): 741–49. http://dx.doi.org/10.1042/bj3250741.
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Genomic clones for Cyp4a12 and a novel member of the murine Cyp4a gene family were isolated. The novel gene, designated Cyp4a14, has a GC rich sequence immediately 5′ of the transcription start site, and is similar to the rat CYP4A2 and CYP4A3 genes. The Cyp4a14 gene spans approximately 13 kb, and contains 12 exons; sequence similarity to the rat CYP4A2 gene sequence falls off 300 bp upstream from the start site. In view of the known sex-specific expression of the rat CYP4A2 gene, the expression and inducibility of Cyp4a14 was examined. The gene was highly inducible in the liver when mice were treated with the peroxisome proliferator, methylclofenapate; induction levels were low in control animals and no sex differences in expression were observed. By contrast, the Cyp4a12 RNA was highly expressed in liver and kidney of control male mice but was expressed at very low levels in liver and kidney of female mice. Testosterone treatment increased the level of this RNA in female liver slightly, and to a greater extent in the kidney of female mice. In agreement with studies on the cognate RNA, expression of Cyp4a12 protein was male-specific in the liver of control mice and extremely high inducibility of Cyp4a10 protein, with no sex differences, was also demonstrated. In view of the overlapping patterns of inducibility of the three Cyp4a genes, we investigated whether the three genes were co-localized in the genome. Two overlapping yeast artificial chromosome (YAC) clones were isolated, and the three Cyp4a genes were shown to be present on a single YAC of 220 kb. The Cyp4a genes are adjacent to the Cyp4b1 gene, with Cyp4a12 most distant from Cyp4b1. The clustering of these two gene subfamilies in the mouse was replicated in the human, where the CYPA411 and CYP4B1 genes were present in a single YAC clone of 440 kb. However, the human CYP4F2 gene was mapped to chromosome 19. Phylogenetic analysis of the CYP4 gene families demonstrated that CYP4A and CYP4B are more closely related than CYP4F.
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Grangeon, Alexia, Valérie Clermont, Azemi Barama, Fleur Gaudette, Jacques Turgeon, and Veronique Michaud. "Determination of CYP450 Expression Levels in the Human Small Intestine by Mass Spectrometry-Based Targeted Proteomics." International Journal of Molecular Sciences 22, no. 23 (2021): 12791. http://dx.doi.org/10.3390/ijms222312791.
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The human small intestine can be involved in the first-pass metabolism of drugs. Under this condition, members of the CYP450 superfamily are expected to contribute to drug presystemic biotransformation. The aim of this study was to quantify protein expression levels of 16 major CYP450 isoforms in tissue obtained from nine human organ donors in seven subsections of the small intestine, i.e., duodenum (one section, N = 7 tissue samples), jejunum (three subsections (proximal, mid and distal), N = 9 tissue samples) and ileum (three subsections, (proximal, mid and distal), N = 9 tissue samples), using liquid chromatography tandem mass spectrometry (LC-MS/MS) based targeted proteomics. CYP450 absolute protein expression levels were compared to mRNA levels and enzyme activities by using established probe drugs. Proteins corresponding to seven of sixteen potential CYP450 isoforms were detected and quantified in various sections of the small intestine: CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, CYP3A5 and CYP4F2. Wide inter-subject variability was observed, especially for CYP2D6. CYP2C9 (p = 0.004) and CYP2C19 (p = 0.005) expression levels decreased along the small intestine. From the duodenum to the ileum, CYP2J2 (p = 0.001) increased, and a trend was observed for CYP3A5 (p = 0.13). CYP3A4 expression was higher in the jejunum than in the ileum (p = 0.03), while CYP4F2 expression was lower in the duodenum compared to the jejunum and the ileum (p = 0.005). CYP450 protein levels were better correlated with specific isoform activities than with mRNA levels. This study provides new data on absolute CYP450 quantification in human small intestine that could improve physiologically based pharmacokinetic models. These data could better inform drug absorption profiles while considering the regional expression of CYP450 isoforms.
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Ciapiene, Ieva, Vacis Tatarunas, Agne Giedraitiene, et al. "The Effect of Rivaroxaban on CYP4F2 and Transcription Factors’ Activity in HUVECs." Applied Sciences 11, no. 22 (2021): 10851. http://dx.doi.org/10.3390/app112210851.
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Interindividual variabilities between patients taking the anticoagulant rivaroxaban are a result of hepatic metabolism by CYP 450 enzymes. The objective of this study was to evaluate the impact of rivaroxaban on CYP4F2 and transcription factors’ activity in HUVECs. Rivaroxaban and its metabolites were detected by UPLC-ESI-MS and UPLC-QTOF-MS. CYP4F2, HNF4α, PXR and CAR expressions were determined in HUVECs by qPCR; CYP4F2 protein concentration was determined by ELISA. Rivaroxaban metabolites (M-1, M-2, M-5, M-8, M-10, M-11 and M-18) were detected in endothelial cells’ culture medium. Increasing concentrations of rivaroxaban determined lower 13-docosenamide concentrations. Rivaroxaban and dexamethasone reduced the expression of CYP4F2 when hsa-miR-24-3p—both CYP4F2 expression and CYP4F2 protein levels in HUVECs. The expression of the transcription factors HNF4α, PXR and CAR was not detected in HUVECs.
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Mota-Zamorano, Sonia, Nicolás R. Robles, Luz M. González, et al. "Genetics Variants in the Epoxygenase Pathway of Arachidonic Metabolism Are Associated with Eicosanoids Levels and the Risk of Diabetic Nephropathy." Journal of Clinical Medicine 10, no. 17 (2021): 3980. http://dx.doi.org/10.3390/jcm10173980.
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Genes in the epoxygenase pathway of arachidonic acid metabolism leading to vasoactive eicosanoids, mainly 20-hydroxyeicosatetraenoic (20-HETE) and epoxyeicosatrienoic (EETs) acids, have been related to glucose-induced renal damage in preclinical reports. We genotyped 1088 diabetic kidney disease (DKD) patients and controls for seven polymorphisms in five genes (CYP2C8, CYP2J2, CYP4F2, CYP4A11, and EPHX2) along this metabolic route and evaluated their effect on DKD risk, clinical outcomes, and the plasma/urine levels of eicosanoids measured by LC/MS/MS and immunoenzymatic assays. The CYP4F2 433M variant allele was associated with lower incidence of DKD (OR = 0.65 (0.48–0.90), p = 0.008), whilst the CYP2C8*3/*3 genotype was related to increased risk (OR = 3.21 (1.05–9.87), p = 0.036). Patients carrying the 433M allele also showed lower eGFR [median and interquartile range vs. wildtype carriers: 30.8 (19.8) and 33.0 (23.2) mL/min/1.73 m2, p = 0.037). Finally, the 433VM/MM variant genotypes were associated with lower urinary levels of 20-HETE compared with 433VV (3.14 (0.86) vs. 8.45 (3.69) ng/mg Creatinine, p = 0.024). Our results indicate that the CYP4F2 V433M polymorphism, by decreasing 20-HETE levels, may play an important role in DKD.
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Nguyen, Xuandai, Mong-Heng Wang, Komandla M. Reddy, John R. Falck, and Michal Laniado Schwartzman. "Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 276, no. 6 (1999): R1691—R1700. http://dx.doi.org/10.1152/ajpregu.1999.276.6.r1691.
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20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome P-450 (CYP) 4A ω-hydroxylation product of arachidonic acid, has potent biological effects on renal tubular and vascular functions and on the control of arterial pressure. We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and -4A8 cDNAs, using baculovirus and Sf 9 insect cells. Arachidonic acid ω- and ω-1-hydroxylations were catalyzed by three of the CYP4A isoforms; the highest catalytic efficiency of 947 nM−1 ⋅ min−1for CYP4A1 was followed by 72 and 22 nM−1 ⋅ min−1for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3 exhibited an additional arachidonate 11,12-epoxidation activity, whereas CYP4A1 operated solely as an ω-hydroxylase. CYP4A8 did not catalyze arachidonic or linoleic acid but did have a detectable lauric acid ω-hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and indicated isoform-specific inhibition. These studies suggest that CYP4A1, despite its low expression in extrahepatic tissues, may constitute the major source of 20-HETE synthesis. Moreover, the ability of CYP4A2 and -4A3 to catalyze the formation of two opposing biologically active metabolites, 20-HETE and 11,12-epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone.
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Kringen, Marianne K., Kari Bente Foss Haug, Runa M. Grimholt, et al. "Genetic Variation of VKORC1 and CYP4F2 Genes Related to Warfarin Maintenance Dose in Patients with Myocardial Infarction." Journal of Biomedicine and Biotechnology 2011 (2011): 1–5. http://dx.doi.org/10.1155/2011/739751.
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The aim of this study was to investigate whether the VKORC1*3 (rs7294/9041 G > A), VKORC1*4 (rs17708472/6009 C > T), and CYP4F2 (rs2108622/1347 C > T) polymorphisms were associated with elevated warfarin maintenance dose requirements in patients with myocardial infarction (n=105) from the Warfarin Aspirin Reinfarction Study (WARIS-II). We found significant associations between elevated warfarin dose requirements and VKORC1*3 and VKORC1*4 polymorphisms (P=.001andP=.004, resp.), whereas CYP4F2 (1347 C > T) showed a weak association on higher warfarin dose requirements (P=.09). However, analysing these variant alleles in a regression analysis together with our previously reported data on VKORC1*2, CYP2C9*2 and CYP2C9*3 polymorphisms, gave no significant associations for neither VKORC1*3, VKORC1*4 nor CYP4F2 (1347 C > T). In conclusion, in patients with myocardial infarction, the individual contribution to warfarin dose requirements from VKORC1*3, VKORC1*4, and CYP4F2 (1347 C > T) polymorphisms was negligible. Our results indicate that pharmacogenetic testing for VKORC1*2, CYP2C9*2 and CYP2C9*3 is more informative regarding warfarin dose requirements than testing for VKORC1*3, VKORC1*4, and CYP4F2 (1347 C > T) polymorphisms.
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Lin, Xianliang, Hao Chen, Le Ni, Yunqiang Yu, Zhurong Luo, and Lihong Liao. "Effects of EPHX1 rs2260863 polymorphisms on warfarin maintenance dose in very elderly, frail Han-Chinese population." Pharmacogenomics 21, no. 12 (2020): 863–70. http://dx.doi.org/10.2217/pgs-2020-0054.
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Aim: This study was conducted to investigate the effects of VKORC1, CYP2C9, CYP4F2 and EPHX1 and nongenetic factors on warfarin maintenance dose in a very elderly, frail Han-Chinese population. Materials & methods: 16 variants of VKORC1, CYP2C9, CYP4F2 and EPHX1 were genotyped. Univariate analysis and multivariable regression model were performed for the associations of gene variants and warfarin maintenance dose. Results & conclusion: EPHX1 rs2260863 nonvariant CC homozygotes required significantly lower daily warfarin dose than GC heterozygotes. In the multivariable model, VKORC1 rs9923231, CYP2C9 rs1057910, EPHX1 rs2260863, CYP4F2 rs2189784 and body surface area altogether explained 26.9% of dosing variability. This study revealed the main impact of genetic factors on warfarin response in this special population.
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Jarrar, Yazun, and Su-Jun Lee. "Effect of rosiglitazone on 20-hydroxyeicosatetraenoic acid levels and CYP4F2 expression in HepG2 cells." Tropical Journal of Pharmaceutical Research 20, no. 4 (2022): 703–8. http://dx.doi.org/10.4314/tjpr.v20i4.6.
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 Purpose: To determine the effect of rosiglitazone on the levels of the cardiotoxic arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), in the human liver hepatocellular carcinoma cell line, HepG2.
 Methods: HepG2 cells were treated with thiazolidinedione rosiglitazone and the mRNA and protein expressions of cytochrome P450 4F2 (CYP4F2) responsible for synthesizing 20-HETE were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The levels of 20-HETE were evaluated using liquid chromatography/mass spectrometry (LC-MS).
 Results: Rosiglitazone significantly increased the levels of CYP4F2 mRNA and protein when compared with the control group (p < 0.05). This was correlated with significantly increased 20-HETE levels in the culture medium of rosiglitazone-treated cells in a dose-dependent manner (p < 0.05). The PPARγ antagonist, GW9662, significantly repressed the increased production of 20-HETE and CYP4F2 mRNA protein (p < 0.05).
 Conclusion: Rosiglitazone increases the synthesis of 20-HETE via activation of PPARγ receptor and upregulation of CYP4F2. These findings may provide an additional explanation, at least in part, for the unwanted side effects of rosiglitazone on the cardiovascular system.
 
 
 
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Ivashchenko, Dmitriy, Ilya Rusin, Dmitriy Sychev, and Andrey Grachev. "The Frequency of CYP2C9, VKORC1, and CYP4F2 Polymorphisms in Russian Patients With High Thrombotic Risk." Medicina 49, no. 12 (2013): 81. http://dx.doi.org/10.3390/medicina49120081.
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Background and Objective. VKORC1, CYP2C9, and CYP4F2 are known to be responsible for the metabolism of warfarin. The aim was to explore the frequencies of these genotypes in the Russian population and compare the results with those for other populations. Material and Methods. In total, 91 Caucasian subjects with a mean age of 66.17 years (SD, 10.9) were recruited into the study. Of them, 40 patients (48.2%) were men. In order to obtain necessary clinical data, the medical records of the patients were reviewed. Blood (5 mL) was taken from each subject, and DNA was isolated and used for identification of the CYP2C9 allele *1, *2, *3, –1639G/A VKORC1, and CYP4F2 V433M rs2108622 C>T, using the real-time polymerase chain reaction-restriction fragment length polymorphism assay. Results. The CYP2C9*1/*1 genotype was detected in 67.0%, CYP2C9*1/*2 in 9.9%, CYP2C9* 1/*3 in 11.0%, CYP2C9*2/*2 in 2.2%, CYP2C9*2/*3 in 8.8%, and CYP2C9*3/*3 in 1.1% of the patients. The results for VKORC1 were as follows: 49.5% (GG), 28.6% (GA), and 22.0% (AA); meanwhile, those for the genotype CYP4F2 were 57.1% (CC), 34.1% (CT), and 7.7% (TT). No significant deviations from the Hardy-Weinberg equilibrium were observed. The frequency of the polymorphisms in the Russian population was found to differ from Asian and close to Caucasian. There were no significant interethnic variations in the frequency of CYP4F2 among Russian, Asian, and Caucasian populations. Conclusion. The frequency of CYP2C9, CYP4F2, and VKORC1 polymorphisms in Russian patients is comparable with other European ethnic groups.
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Bairova, T. A., E. A. Novikova, F. I. Belyalov, et al. "FREQUENCIES OF POLYMORPHISMS IN THE CYTOCHROME’S P450 GENES OF WARFARIN TRANSFORMATION IN A EUROPEAN POPULATION OF EASTERN SIBERIA." Acta Biomedica Scientifica 3, no. 5 (2018): 39–48. http://dx.doi.org/10.29413/abs.2018-3.5.6.
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Background.Genotypes of the cytochrome p450 isoform (CYP2C9 and CYP4F2) determine warfarin dose requirements. Frequencies of risk alleles and genotypes of CYP2C9 and CYP4F2 gene vary in different races and ethnic groups.Aim.This study analyzed the frequencies of *2, *3 alleles of CYP2C9 gene and the 1347 C>T allele of CYP4F2 gene in the Caucasians of Eastern Siberia, and compare with other populations.Materials and methods.Participants were 147 patients (Caucasians): 67 (45.58 %) man and 80 (54.42 %) women), taking warfarin for the prevention of thrombosis with a mean age of 64.74 ± 14.29 years. There were patients with atrial fibrillation – 77 (52.38 %) persons, coronary artery disease – 10 (6.80 %), pulmonary embolism – 5 (3.40 %), 15 (10.20 %) patients after implantation of an mechanical heart valve, etc. The subjects were genotyped for CYP2C9 (*1,*2,*3), and CYP4F2 (1347 C>T) by real-time polymerase chain reaction (RT-PCR) using “Pharmacogenetics Warfarin” reagent kits (DNA technology, Russia).Results.69.4 % of Caucasians of Eastern Siberia (Russians), have two functional alleles (*1/*1) of CYP2C9 (they’re extensive/normal metabolizers), the number of intermediate metabolizers (*1/*2, *1/*3) was 29.8 % and 0.68 % of slow metabolizers (*3/*3). Homozygous carriers of two non-functional alleles *2 and *3 (*2/*2, *2/*3) were absent. Carriers of one coumarin-resistant Т-allele of CYP4F2 were 57 (38.7 %) respondents, two coumarin-resistant alleles – 10 (6.8 %) respondents.Conclusions.Frequencies of polymorphisms in the Cytochrome’s p450 genes of warfarin transformation in a European population of Eastern Siberia have no differences with other European populations of the world
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Stec, David E., Richard J. Roman, Averia Flasch, and Mark J. Rieder. "Functional polymorphism in human CYP4F2 decreases 20-HETE production." Physiological Genomics 30, no. 1 (2007): 74–81. http://dx.doi.org/10.1152/physiolgenomics.00003.2007.
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20-Hydroxyeicosatetraenoic acid (20-HETE) plays an important role in the regulation of renal tubular and vascular function and a deficiency in the renal formation of 20-HETE has been linked to the development of hypertension. The cytochrome P450 4F2 ( CYP4F2) gene encodes for the major CYP enzyme responsible for the synthesis of 20-HETE in the human kidney. We screened two human sampling panels (African and European Americans: n = 24 and 23 individuals, respectively) using PCR and DNA resequencing to identify informative SNPs in the coding region of the CYP4F2 gene. Two nonsynonymous SNPs that lead to amino acid changes at position 12 (W12G) and 433 (V433M), were identified. Both of these variants were found to be frequent in both African and European American sampling panels (9–21% minor allele frequency), and the W12G polymorphism exhibited extensive linkage disequilibrium with surrounding SNPs. To determine the functional significance of these mutations on the ability of the CYP4F2 enzyme to metabolize arachidonic acid and leukotriene B4 (LTB4), recombinant baculoviruses containing four different human CYP4F2 variants (i.e., W12/V433, W12/M433, G12/V433, G12/M433) were generated and the proteins were expressed in Sf9 insect cells. The presence of the M433 allele, W12/M433, or G12/M433 decreased 20-HETE production to 56–66% of control. In contrast these variants had no effect on the ω-hydroxylation of LTB4. These findings are the first to identify a functional variant in the human CYP4F2 gene that alters the production of 20-HETE.
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Rojo, Mario, Angela Margarita Roco, Marcelo Suarez, et al. "Functionally Significant Coumarin-Related Variant Alleles and Time to Therapeutic Range in Chilean Cardiovascular Patients." Clinical and Applied Thrombosis/Hemostasis 26 (January 1, 2020): 107602962090915. http://dx.doi.org/10.1177/1076029620909154.
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Despite the development of new oral agents over the last decade, vitamin K antagonists (VKAs) remain the most widely used anticoagulants for treating and preventing thromboembolism worldwide. In Chile, the Ministry of Health indicates that acenocoumarol should be used in preference to any other coumarin. Complications of inappropriate dosing are among the most frequently reported adverse events associated with this medication. It is well known that polymorphisms in pharmacokinetic and pharmacodynamic proteins related to coumarins (especially warfarin) influence response to these drugs. This work analyzed the impact of CYP2C19*2 ( rs4244285), CYP1A2*1F ( rs762551), GGCx ( rs11676382), CYP2C9*2 ( rs1799853), CYP2C9*3 ( rs1057910), CYP4F2 ( rs2108622), VKORC1 ( rs9923231), VKORC1 ( rs7294), CYP3A4*1B ( rs2740574), and ABCB1 ( rs1045642) polymorphisms on time to therapeutic range for oral anticoagulants in 304 Chilean patients. CYP2C9*3 polymorphisms were associated with time to therapeutic range for acenocoumarol in Chilean patients, and the CYP4F2 TT genotype, MDR1 A allele, CYP1A2 A allele, and CYP3A4T allele are promising variants that merit further analysis. The presence of polymorphisms explained only 4.1% of time to therapeutic range for acenocoumarol in a multivariate linear model. These results improve our understanding of the basis of ethnic variations in drug metabolism and response to oral anticoagulant therapy. We hope that these findings will contribute to developing an algorithm for VKA dose adjustment in the Chilean population in the near future, decreasing the frequency of stroke, systemic embolism, and bleeding-related adverse events.
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Vesa, Stefan Cristian, Sonia Irina Vlaicu, Vitalie Vacaras, et al. "CYP4F2 and VKORC1 Polymorphisms Amplify the Risk of Carotid Plaque Formation." Genes 11, no. 7 (2020): 822. http://dx.doi.org/10.3390/genes11070822.
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Introduction: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of atherosclerosis, we decided to investigate whether polymorphisms in genes that influence vitamin K metabolism might have an impact in modulating the risk of plaque formation. Patients and Methods: In the current study we included adult patients admitted in the Clinical Municipal Hospital of Cluj-Napoca without any carotid or femoral plaques clinically visible at the initial investigation, and a five year follow-up was subsequently performed. We recorded the following patient characteristics: age at inclusion, gender, area of living, smoking, presence of carotid and/or femoral plaques at five years, ischemic heart disease, arterial hypertension, atrial fibrillation, heart failure, diabetes mellitus, obesity, dyslipidemia, drug (oral anticoagulants, antihypertensives, hypolipidemic, anti-diabetic) use and status for the following gene polymorphisms: VKORC1 1639 G>A, CYP4F2 1347 G>T and GGCX 12970 C>G. Results: We observed that the major predictor of both carotid and femoral plaque formation is represented by ischemic cardiac disease. VKORC1 and CYP4F2 polymorphisms did not predict plaque formation, except for VKORC1 homozygous mutants. Nonetheless, both VKORC1 and CYP4F2 interacted with ischemic cardiac disease, increasing the risk of developing a carotid plaque, while only CYP4F2, but not VKORC1, interacted with ischemic cardiac disease to increase the risk of femoral plaque formation. Conclusions: We documented that CYP4F2 and VKORC1 polymorphisms boost the proinflammatory plaque environment (observed indirectly through the presence of ischemic heart disease), increasing the risk of plaque development.
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Kolesnik, M. Yu, and Yа М. Mykhailovskyi. "Frequencies of polymorphisms in genes affecting the pharmacokinetics of warfarin in the Zaporizhzhia region." Zaporozhye Medical Journal 23, no. 4 (2021): 476–79. http://dx.doi.org/10.14739/2310-1210.2021.4.227002.
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The aim of the study: to establish the frequencies of polymorphisms in VKORC1, CYP2C9 and CYP4F2 genes among residents of the Zaporizhzhia region. Materials and methods. A total of 150 persons (62 male, 88 female) with a median age of 46 years (26; 58) undergoing preventive examination at the Medical Educational and Scientific Center “University Clinic” of Zaporizhzhia State Medical University (ZSMU). The CYP2C9, CYP4F2, VKORC1 genes polymorphisms in atrial fibrillation patients were determined in the Department of Molecular Genetic Studies of the ZSMU Medical Laboratory Center. Amplification of DNA fragments containing polymorphic regions was performed using multiplex real time polymerase chain reaction with Warfarin Pharmacogenetics kits (LLC NPO DNA Technology) in a CFX-96 thermocycler (BioRad) with a fluorescence detection scheme. Results. It was determined that among Zaporizhzhia region residents, the frequencies of CYP2C9*2 genotypes were: C/C – 77.3 %, C/T – 22.7 %, T/T – 0; CYP2C9*3 genotypes: A/A – 88.7 %, A/C – 10.7 %, C/C – 0.6 %; CYP4F2 genotypes: C/C – 56.0 %, C/T – 35.3 %, T/T – 8.7 %; VKORC1 genotypes: G/G – 38.0 %, G/A – 50.0 %, A/A – 12.0 %. There were no statistically significant differences in the distribution of genotype frequencies between males and females and between different age groups. The frequencies of CYP2C9, CYP4F2, VKORC1 genotypes in different populations were compared. Their variability in different geographic regions was established. Conclusions. CYP4F2 and VKORC1 genes polymorphisms are more common in the Zaporizhzhia region, while the prevalence of CYP2C9*2 and CYP2C9*3 genes polymorphisms is much lower. It is necessary to take into account the prevalence of genes polymorphisms that affect warfarin metabolism for each individual population to select its dose by pharmacogenetic testing.
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Wang, Mong-Heng, Hui Guan, Xuandai Nguyen, Barbara A. Zand, Alberto Nasjletti, and Michal Laniado-Schwartzman. "Contribution of cytochrome P-450 4A1 and 4A2 to vascular 20-hydroxyeicosatetraenoic acid synthesis in rat kidneys." American Journal of Physiology-Renal Physiology 276, no. 2 (1999): F246—F253. http://dx.doi.org/10.1152/ajprenal.1999.276.2.f246.
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20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active cytochrome P-450 (CYP) metabolite of arachidonic acid in the rat kidney, can be catalyzed by CYP4A isoforms including CYP4A1, CYP4A2, and CYP4A3. To determine the contribution of CYP4A isoforms to renal 20-HETE synthesis, specific antisense oligonucleotides (ODNs) were developed, and their specificity was examined in vitro in Sf9 cells expressing CYP4A isoforms and in vivo in Sprague-Dawley rats. Administration of CYP4A2 antisense ODNs (167 nmol ⋅ kg body wt−1 ⋅ day−1iv for 5 days) decreased vascular 20-HETE synthesis by 48% with no effect on tubular synthesis, whereas administration of CYP4A1 antisense ODNs inhibited vascular and tubular 20-HETE synthesis by 52 and 40%, respectively. RT-PCR of microdissected renal microvessel RNA indicated the presence of CYP4A1, CYP4A2, and CYP4A3 mRNAs, and a CYP4A1-immunoreactive protein was detected by Western analysis of microvessel homogenates. Blood pressure measurements revealed a reduction of 17 ± 6 and 16 ± 4 mmHg in groups receiving CYP4A1 and CYP4A2 antisense ODNs, respectively. These studies implicate CYP4A1 as a major 20-HETE synthesizing activity in the rat kidney and further document the feasibility of using antisense ODNs to specifically inhibit 20-HETE synthesis and thereby investigate its role in the regulation of renal function and blood pressure.
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Lai, Guangrui, Jingjing Wu, Xiaoliang Liu, and Yanyan Zhao. "20-HETE Induces Hyperglycemia through the cAMP/PKA-PhK-GP Pathway." Molecular Endocrinology 26, no. 11 (2012): 1907–16. http://dx.doi.org/10.1210/me.2012-1139.
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Abstract We previously generated cytochrome P450 4F2 (CYP4F2) transgenic mice and showed high 20-hydroxyeicosatetraenoic acid (20-HETE) production, which resulted in an elevation of blood pressure. However, it was unclear whether 20-HETE affected glucose metabolism. We measured fasting plasma glucose, insulin, hepatic CYP4F2 expression, and 20-HETE production by hepatic microsomes, and hepatic 20-HETE levels in transgenic mice. We also assessed glycogen phosphorylase (GP) activity and the cAMP/protein kinase A (PKA)-phosphorylase kinase (PhK)-GP pathway, as well as expressions of insulin receptor substrate 1 and glucose transporters in vivo and in vitro. The transgenic mice had overexpressed hepatic CYP4F2, high hepatic 20-HETE and fasting plasma glucose levels but normal insulin level. The GP activity was increased and the cAMP/PKA-PhK-GP pathway was activated in the transgenic mice compared with wild-type mice. Moreover, these alterations were eliminated with the addition of N-hydroxy-N′-(4-butyl-2 methylphenyl) formamidine, which is a selective 20-HETE inhibitor. The results were further validated in Bel7402 cells. In addition, the transgenic mice had functional insulin signaling, and 20-HETE had no effect on insulin signaling in Bel7402 cells, excluding that the observed hyperglycemia in CYP4F2 transgenic mice resulted from insulin dysfunction, because the target tissues were sensitive to insulin. Our study suggested that 20-HETE can induce hyperglycemia, at least in part, through the cAMP/PKA-PhK-GP pathway but not through the insulin-signaling pathway.
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Si, Lining, Haiyuan Wang, Rong Wang, et al. "Suggestive evidence of CYP4F2 gene polymorphisms with HAPE susceptibility in the Chinese Han population." PLOS ONE 18, no. 1 (2023): e0280136. http://dx.doi.org/10.1371/journal.pone.0280136.
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High altitude pulmonary edema (HAPE) is a common respiratory disease in the high altitude area, which is rapid and harmful. We firstly conducted a case-control study to assess the potential association of CYP4F2 gene polymorphisms with HAPE susceptibility in the Chinese Han population. The study recruited 238 patients with HAPE and 230 healthy controls in Northwest China. Genomic DNA was extracted from blood samples, and gene polymorphisms were detected using the Agena MassARRAY platform. Odds ratios (ORs), 95% confidence intervals (95% CIs), and P-value were used to evaluate the relationship between HAPE risk and CYP4F2 gene polymorphisms. Multi-factor dimension reduction (MDR) was used to assess the optimal interaction of CYP4F2 gene polymorphisms on HAPE risk. We found rs3093193 was shown to reduce the risk of HAPE (OR = 0.70, 95% CI = 0.52–0.93, P = 0.014), while rs12459936 was increased the susceptibility to HAPE (OR = 2.08, 95% CI = 1.33–3.26, P = 0.001). Age stratified analysis revealed that rs3093193 and rs12459936 were correlated with HAPE risk in people at age > 32 years old, and rs3093193 and rs3093110 were correlated with the HAPE risk in people at age ≤ 32 years old. Gender stratification analysis was found that rs3093193, rs12459936, and rs3093110 were all related to HAPE risk in males. A combination of rs12459936 and rs3093110 was the best multi-loci model with the highest testing accuracy. Our study is the first to provide the association between CYP4F2 gene polymorphisms and HAPE risk in the Chinese Han population.
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Mirzaev, K. B., D. S. Fedorinov, D. V. Ivashchenko, and D. A. Sychev. "Multi-Ethnic Analysis of Cardiac Pharmacogenetic Markers of Cytochrome P450 and Membrane Transporters Genes in the Russian Population." Rational Pharmacotherapy in Cardiology 15, no. 3 (2019): 393–406. http://dx.doi.org/10.20996/1819-6446-2019-15-3-393-406.
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Aim. To summarize Russian studies using pharmacogenetic testing as applied to cardiology.Material and methods. The authors conducted an online search for articles in December 2018 using the following databases: PubMed, Google Scholar, eLIBRARY. The search was carried out by keywords: "Russia", "Russian", "cardiology" together with the terms associated with the polymorphic marker, including: «P450», «CYP2C19», «CYP2D6», «CYP2B1», «CYP2B6», «CYP2Е1», «CYP2C8», «CYP2C9», «CYP3A4», «CYP3A5», «CYP1A1», «CYP1A2», «CYP4F2», «CYP4F1», «ABCB1», «SLCO1B1», «VKORC1», «GGCX», «SULT1A1», «CULT1», «CES1», «gene», «genes», «pharmacogenetics», «pharmacogenomics», «ethnic group».Results. Generalization of information allowed to identify obscure genes that need to be investigated in pharmacogenetic studies. This information can be used for the development of dosing algorithms and the priority choice of drugs, considering the results of pharmacogenetic testing and planning future research.Conclusion. The results of the literature review indicate the importance of studying the most clinically valid and clinically useful pharmacogenetic markers (CYP2C19, CYP2C9, VKORC1, SLCO1B1) among various ethnic groups in the Russian Federation. With the accumulation of evidence of clinical validity and clinical utility of other pharmacogenetic markers (CES1, CYP2D6*4, etc.), the problem of interethnic differences in the carriage of clinically significant polymorphisms of these genes identified in previous studies in the Russian Federation increasingly requires attention. The most promising for the introduction into the clinical practice in the Russian Federation in the near future are polymorphic markers of the CYP2C19, CYP2C9, VKORC1 and SLCO1B1 genes.
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LUNDELL, Kerstin. "Cloning and expression of two novel pig liver and kidney fatty acid hydroxylases [cytochrome P450 (CYP)4A24 and CYP4A25]." Biochemical Journal 363, no. 2 (2002): 297–303. http://dx.doi.org/10.1042/bj3630297.
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A new member of the cytochrome P450 (CYP) 4A subfamily (CYP4A21) was recently cloned by PCR from pig liver [Lundell, Hansson, and Wikvall (2001) J. Biol. Chem. 276, 9606–9612]. This enzyme does not catalyse ω- or (ω-1)-hydroxylation of lauric acid, the model substrate for CYP4A enzymes. Instead, CYP4A21 participates in bile acid biosynthesis in the pig. Extensive studies, primarily conducted to verify the aberrant amino acids found in CYP4A21 within a normally conserved CYP4A motif, revealed that besides CYP4A21 two additional sequences were co-amplified by PCR. These two sequences (designated CYP4A24 and CYP4A25), generated from both pig liver and kidney, were characterized by restriction-enzyme analysis and were subsequently cloned. The deduced amino acid sequences of CYP4A24 and CYP4A25 share extensive sequence identity (97%). Both enzymes, expressed in yeast cells, exhibit ω-and (ω-1)-hydroxylase activities towards lauric acid and palmitic acid. The positions of the variable regions between CYP4A24 and CYP4A25, which are confined to β-sheets 1 and 4, indicate a possible difference in substrate specificity or regioselectivity. The porcine CYP4A21, CYP4A24 and CYP4A25 enzymes, with an overall identity of 94%, have probably evolved from a common ancestral gene, perhaps in conjunction with species-specific habits.
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Xu, Shang-Fu, An-Ling Hu, Lu Xie, Jia-Jia Liu, Qin Wu, and Jie Liu. "Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats." PeerJ 7 (August 2, 2019): e7429. http://dx.doi.org/10.7717/peerj.7429.
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Cytochrome P450s (CYPs) are phase-I metabolic enzymes playing important roles in drug metabolism, dietary chemicals and endogenous molecules. Age is a key factor influencing P450s expression. Thus, age-related changes of CYP 1–4 families and bile acid homeostasis-related CYPs, the corresponding nuclear receptors and a few phase-II genes were examined. Livers from male Sprague-Dawley rats at fetus (−2 d), neonates (1, 7, and 14 d), weanling (21 d), puberty (28 and 35 d), adulthood (60 and 180 d), and aging (540 and 800 d) were collected and subjected to qPCR analysis. Liver proteins from 14, 28, 60, 180, 540 and 800 days of age were also extracted for selected protein analysis by western blot. In general, there were three patterns of their expression: Some of the drug-metabolizing enzymes and related nuclear receptors were low in fetal and neonatal stage, increased with liver maturation and decreased quickly at aging (AhR, Cyp1a1, Cyp2b1, Cyp2b2, Cyp3a1, Cyp3a2, Ugt1a2); the majority of P450s (Cyp1a2, Cyp2c6, Cyp2c11, Cyp2d2, Cyp2e1, CAR, PXR, FXR, Cyp7a1, Cyp7b1. Cyp8b1, Cyp27a1, Ugt1a1, Sult1a1, Sult1a2) maintained relatively high levels throughout the adulthood, and decreased at 800 days of age; and some had an early peak between 7 and 14 days (CAR, PXR, PPARα, Cyp4a1, Ugt1a2). The protein expression of CYP1A2, CYP2B1, CYP2E1, CYP3A1, CYP4A1, and CYP7A1 corresponded the trend of mRNA changes. In summary, this study characterized three expression patterns of 16 CYPs, five nuclear receptors, and four phase-II genes during development and aging in rat liver, adding to our understanding of age-related CYP expression changes and age-related disorders.
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Park, Jin‐Woo, Kyoung‐Ah Kim, and Ji‐Young Park. "Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F2*3 Genetic Polymorphism on Pharmacokinetics of Vitamin K 1." Journal of Clinical Pharmacology 59, no. 11 (2019): 1453–61. http://dx.doi.org/10.1002/jcph.1444.
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Wei, Meng, Fei Ye, Dujiang Xie, et al. "A new algorithm to predict warfarin dose from polymorphisms of CYP4F2, CYP2C9 and VKORC1 and clinical variables: Derivation in Han Chinese patients with non valvular atrial fibrillation." Thrombosis and Haemostasis 107, no. 06 (2012): 1083–91. http://dx.doi.org/10.1160/th11-12-0848.
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SummaryFew pharmacogenomic dosing regimens of warfarin have been developed for Chinese patients with non valvular atrial fibrillation (NVAF). The objective of this study was to develop a new algorithm by polymorphisms of CYP2C9, VKORC1 and CYP4F2 to predict the daily stable dose of warfarin in Chinese patients with NVAF. A total of 325 Chinese NVAF patients on stable dose of warfarin with a target international normalised ratio of 1.5 to 3.0 were recruited and divided randomly into two cohorts. CYP2C9*3, VKORC1 –1639, VKORC1 1173 and CYP4F2 were detected by ligase detection reaction method. The new algorithm was developed with multivariate linear regression in cohort 1 (260 patients) and assessed with Pearson Correlation Analysis (PCA) in cohort 2 (65 patients). From 260 enrolled patients, the model (R2 = 51.7%) was developed as: Dose = 3.47 − 0.022 (AGE) + 0.017 (WT) + 0.189 (PTE) − 0.283 (β-blocker) − 0.471 (AMIO) − 0.586 (CYP2C9 *1/*3) − 0.296 (VKORC1 CT) – 0.648 (VKORC1 TT) + 0.219 (CYP4F2 TT). PCA displayed that the algorithm was good (r = 0.658). The residual plots revealed that the predicted doses by the algorithm tend to be overestimated when lower doses were administered to patients and to be underestimated in higher doses. The algorithm developed by us might predict warfarin dose used by Chinese NVAF patients.
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Caldwell, Michael D., Tarif Awad, Julie A. Johnson, et al. "CYP4F2 genetic variant alters required warfarin dose." Blood 111, no. 8 (2008): 4106–12. http://dx.doi.org/10.1182/blood-2007-11-122010.
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Abstract Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450 4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.
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Banevicius, Mantas, Alvita Vilkeviciute, Brigita Glebauskiene, Loresa Kriauciuniene, and Rasa Liutkeviciene. "Association of Optic Neuritis with CYP4F2 Gene Single Nucleotide Polymorphism and IL-17A Concentration." Journal of Ophthalmology 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/1686297.
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Background. The aetiology and pathophysiology of optic neuritis (ON) is not absolutely clear but genetic and inflammatory factors may be also involved in its development. The aim of the present study was to determine the influence of single nucleotide polymorphism (SNP) of CYP4F2 (rs1558139) and serum levels of IL-17A on ON development. Materials and Methods. Forty patients with ON and 164 control subjects were evaluated. Patients were divided by gender, also ON patients were divided into two subgroups: ON with and without multiple sclerosis (MS). CYP4F2 rs1558139 was genotyped using real-time PCR. Serum IL-17A levels were measured using ELISA IL-17A kits. Results. We found that A/A genotype of CYP4F2 rs1558139 was statistically significantly more frequent in men with ON and MS than in women: 57.1% versus 0%, p=0.009. Also, allele A was statistically significantly more frequent in men with ON and MS than in women: 71.4% versus 37.5%, p=0.044. Serum levels of IL-17A were higher in ON group than in control group: (median, IQR): 20.55 pg/ml, 30.66 pg/ml versus 8.97 pg/ml, 6.24 pg/ml, p<0.001. Conclusion. The higher IL-17A levels were found to be associated with ON, while allele A at rs1558139 was associated only with ON with MS in male patients.
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Vear, Susan I., Gregory D. Ayers, C. Michael Stein, and Richard H. Ho. "Polymorphisms in VKORC1, CYP2C9, and CYP4F2 and Warfarin Dose in the Pediatric Population." Blood 120, no. 21 (2012): 4358. http://dx.doi.org/10.1182/blood.v120.21.4358.4358.
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Abstract Abstract 4358 Objective Warfarin is an oral vitamin K antagonist commonly used in pediatric patients who require anticoagulation. Studies in adults receiving warfarin demonstrate that polymorphisms in 2 genes involved in warfarin disposition and response, cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1), explain 30–40% of the variation in stable dose. Recent evidence suggests a role for a cytochrome P450 4F2 (CYP4F2) variant in altered warfarin disposition. These associations have not been well-studied in the pediatric population. We hypothesized that polymorphic variants in CYP2C9, VKORC1, and CYP4F2 are associated with interindividual variability in stable warfarin dose in pediatric patients. Methods We designed a cross-sectional study examining the relationship between stable warfarin dose and commonly occurring polymorphisms in CYP2C9 (*2 and *3), VKORC1 (haplotype A, comprised of 5 promoter and intronic variants), and CYP4F2 (variant allele T) in children. Patients <25 years old who had begun, received, or completed warfarin therapy at <20 years were eligible for recruitment. Patients were identified in 2 ways: a search of our institutional electronic medical record (StarPanel) or a search of the Synthetic Derivative (SD), the deidentified electronic medical record which correlates to the Vanderbilt BioVU DNA biorepository, a DNA databank with >16,000 pediatric DNA samples. Patients identified from StarPanel were approached at a Vanderbilt clinic appointment or by mail/phone call for enrollment. Data was collected via study questionnaire and review of StarPanel, including demographic factors and covariates such as concomitant medications, co-morbidities, warfarin indication, and diet history. Warfarin dose and INR history were also collected. The same information, excluding study questionnaire data, was collected from the SD for the BioVU population. The BioVU and StarPanel populations were cross-referenced to prevent inclusion of duplicate patients. Genomic DNA was extracted from peripheral blood lymphocytes obtained from blood drawn with routine labs or from epithelial cells from a saliva sample. All samples were genotyped for CYP2C9, VKORC1, and CYP4F2 variants using a validated Taqman-based PCR method. Results One-hundred seventeen patients (45 StarPanel, 72 BioVU) with mean age 12.5 years at time of stable warfarin dose were recruited and met eligibility criteria for inclusion. 55.6% of the patients were female and the majority (82.9%) were Caucasian, though African-Americans (10.3%) and other minorities were also represented. The majority of patients had DVT (47%) or prosthetic valve (26.5%) as indications for warfarin therapy. There was a statistically significant correlation between height and stable warfarin dose (r=-0.346, p<0.0001). Sixteen patients (13.6%) had bleeding complications while on warfarin, 8 of whom required hospitalization. No bleeding event resulted in death or long-term sequelae. Two patients had more than 1 bleeding event reported. Four patients (3.4%) had thrombosis while on warfarin. Two of the 4 received no additional therapy and had complete resolution of symptoms. No thrombotic event resulted in death. Genotype analysis for CYP2C9, VKORC1, and CYP4F2 variants has been completed in the StarPanel population, and genotyping in the BioVU population is currently being completed. To date, variant allele frequencies are similar to published population frequencies, with 38.6% VKORC1 haplotype A, 10.5% CYP2C9*2, 4.7% CYP2C9*3, and 32.3% CYP4F2 haplotype T. Preliminary analysis supports previously published data indicating a role for genotype in warfarin sensitivity in children (Figure 1). Patients homozygous for the VKORC1 A haplotype tended to require a lower warfarin dose to achieve target INR. Patients with variant CYP alleles (CYP2C9*2, CYP2C9*3, or CYP4F2 variant T) tended to require lower warfarin doses to achieve target INR. VKORC1 appeared to demonstrate a gene dosage effect with a lower dose requirement for each variant allele present. Our results suggest polymorphisms in VKORC1 and CYP2C9 contribute to altered warfarin disposition and response in pediatric patients. Disclosures: No relevant conflicts of interest to declare.
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Yanes, Licy L., Roberta Lima, Mohadetheh Moulana, et al. "Postmenopausal hypertension: role of 20-HETE." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 300, no. 6 (2011): R1543—R1548. http://dx.doi.org/10.1152/ajpregu.00387.2010.
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Blood pressure (BP) increases after menopause. However, the mechanisms responsible have not been elucidated. In this study we tested the hypothesis that 20-hydroxyeicosatetraenoic acids (20-HETE), produced by cytochrome P-450 (CYP450) ω-hydroxylase, contributes to the hypertension in a model of postmenopausal hypertension, aged female spontaneously hypertensive rats (PMR). 1-Aminobenzotriazole, a nonselective inhibitor of arachidonic acid metabolism, for 7 days, reduced BP in PMR but had no effect in young females. Acute intravenous infusion of HET-0016, a specific inhibitor of 20-HETE, over 3 h, also reduced BP in PMR. CYP4A isoform mRNA expression showed no difference in renal CYP4A1 or CYP4A3 but increases in CYP4A2 and decreases in CYP4A8. CYP4A protein expression was decreased in kidney of PMR compared with young females. Endogenous 20-HETE was significantly higher in cerebral vessels of PMR than young females (YF) but was significantly lower in renal vessels of PMR. Omega-hydroxylase activity in cerebral vessels was also higher in PMR but was similar in kidney vessels in both groups. In renal microsomal preparations, endogenous 20-HETE was not different in PMR and young females, but ω-hydroxylase activity was significantly lower in PMR than YF. The data with blockers suggest that 20-HETE contributes to postmenopausal hypertension in SHR. The data also suggest that cerebral production of 20-HETE may be increased and renal tubular production may be decreased in PMR, thus both contributing to their elevated BP.
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Sambyalova, A. Yu, T. A. Bairova, E. V. Belyaeva, O. A. Ershova, D. S. Sargaeva, and S. I. Kolesnikov. "CYP2C9, CYP4F2, VKORC1 Gene Polymorphism in Buryat Population." Russian Journal of Genetics 56, no. 12 (2020): 1496–503. http://dx.doi.org/10.1134/s1022795420120121.
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Самбялова, А. Ю., Т. А. Баирова, Е. В. Беляева, О. А. Ершова, Д. С. Саргаева та С. И. Колесников. "Полиморфизм генов CYP2C9 , CYP4F2 , VKORC1 в популяции бурят". Генетика 56, № 12 (2020): 1427–34. http://dx.doi.org/10.31857/s0016675820120127.
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Shekhar, Shashank, Kevin Varghese, Man Li, et al. "Conflicting Roles of 20-HETE in Hypertension and Stroke." International Journal of Molecular Sciences 20, no. 18 (2019): 4500. http://dx.doi.org/10.3390/ijms20184500.
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Hypertension is the most common modifiable risk factor for stroke, and understanding the underlying mechanisms of hypertension and hypertension-related stroke is crucial. 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE), which plays an important role in vasoconstriction, autoregulation, endothelial dysfunction, angiogenesis, inflammation, and blood-brain barrier integrity, has been linked to hypertension and stroke. 20-HETE can promote hypertension by potentiating the vascular response to vasoconstrictors; it also can reduce blood pressure by inhibition of sodium transport in the kidney. The production of 20-HETE is elevated after the onset of both ischemic and hemorrhagic strokes; on the other hand, subjects with genetic variants in CYP4F2 and CYP4A11 that reduce 20-HETE production are more susceptible to stroke. This review summarizes recent genetic variants in CYP4F2, and CYP4A11 influencing 20-HETE production and discusses the role of 20-HETE in hypertension and the susceptibility to the onset, progression, and prognosis of ischemic and hemorrhagic strokes.
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Pérez-Andreu, Virginia, Vanessa Roldán, Ana Isabel Antón, et al. "Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy." Blood 113, no. 20 (2009): 4977–79. http://dx.doi.org/10.1182/blood-2008-09-176222.
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VKORC1 and CYP2C9 polymorphisms are used to predict the safe dose of oral anticoagulant therapy. A new variant of CYP4F2 (V433M) has recently been related to the required warfarin dose. We evaluated its influence in earliest response to acenocoumarol in 100 selected men who started anticoagulation (3 mg for 3 consecutive days). V433M genotype exerted a gene dosage-dependent effect on the decrease of factors II, VII, IX, and X in the earliest response to acenocoumarol, with homozygous 433V subjects being the most sensitive. Similarly, after the initiation of therapy, international normalized ratio also experienced a gene dosage-dependent effect (P = .015), and 433V subjects needed 4 mg/week less than 433M carriers to achieve a steady anticoagulation (P = .043). Multivariate linear regression analysis revealed a significant contribution of V433M polymorphism to variability of both early international normalized ratio value (R2 = 0.14) and dose requirements (R2 = 0.19). Our data underline the relevant role of CYP4F2 V433M polymorphism in the pharmacogenetics of coumarin anticoagulants.
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Moreau, Caroline, Eric Pautas, Charlotte Duverlie, et al. "A model predicting fluindione dose requirement in elderly inpatients including genotypes, body weight, and amiodarone." Thrombosis and Haemostasis 111, no. 04 (2014): 705–12. http://dx.doi.org/10.1160/th13-07-0555.
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SummaryIndandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 ± 6 years, who had reached international normalized ratio stabilisation (range 2.0–3.0) on fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non-genetic and genetic data and evaluated the model performances in a separate cohort (n=74). Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e. the usual step used for adjusting fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1,CYP4F2,ABCB1) related to the pharmacodynamic effect and transport of fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins.
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Kikuta, Y., E. Kusunose, and M. Kusunose. "Characterization of Human Liver Leukotriene B4 -Hydroxylase P450 (CYP4F2)." Journal of Biochemistry 127, no. 6 (2000): 1047–52. http://dx.doi.org/10.1093/oxfordjournals.jbchem.a022696.
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Mak, May, Carol Lam, Sandra J. Pineda, et al. "Pharmacogenetics of Warfarin in a Diverse Patient Population." Journal of Cardiovascular Pharmacology and Therapeutics 24, no. 6 (2019): 521–33. http://dx.doi.org/10.1177/1074248419843530.
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Introduction: Many warfarin-related genotypes have shown to impact the average daily warfarin (ADW) dose requirements; however, information in non-Caucasian populations is limited. Objectives: To identify the frequencies of 4 warfarin-related gene polymorphisms in an ethnically diverse patient population and to examine their impact with other clinical variables on ADW dose requirements. Methods: Patients were recruited from 2 anticoagulation clinics in the Los Angeles area. Blood samples were collected and genotyped for vitamin K epoxide reductase (VKORC1), CYP2C9*2, CYP2C9*3, and CYP4F2 after informed consent. Charts were reviewed to collect demographic, clinical, and warfarin dosing data. Results: A total of 291 patients were included (120 Caucasians, 127 Hispanics, and 44 Asians). In patients with wild-type genotypes for VKORC1, CYP2C9*2, CYP2C9*3, and CYP4F2, the highest warfarin requirement was found in Caucasians, lower in Hispanics, and lowest in Asians. Homozygous VKORC1 variant carriers were detected in 15%, 15%, and 79% in Caucasians, Hispanics, and Asians, respectively. Progressive lowering of ADW doses were associated with each VKORC1 variant in Caucasians and Hispanics, but the results in wild-type/ heterozygote Asians were unclear. CYP2C9 variants were associated with lower ADW doses; frequencies of CYP2C9*2 and CYP2C9*3 mutations were higher in Caucasians than in Hispanics but rare to none in Asians. The frequencies of CYP4F2 variant were similar across all ethnicities, but their impact on warfarin dose requirement were insignificant. Clinical factors such as age, body surface area, history of coronary artery disease, deep vein thrombosis or atrial fibrillation, and concomitant amiodarone or HMG-CoA reductase inhibitors had varying impact on the ADW requirements in the ethnicities studied. Conclusions: Our study demonstrated differences among 3 ethnic groups in terms of ADW dose requirements and the impact of associated clinical variables. The results suggest that a single model for all ethnicities may not provide the best performance in predicting warfarin dose requirements.
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Yan, H. Q., Y. Yuan, P. Zhang, Z. Huang, L. Chang, and Y. K. Gui. "CYP4F2 gene single nucleotide polymorphism is associated with ischemic stroke." Genetics and Molecular Research 14, no. 1 (2015): 659–64. http://dx.doi.org/10.4238/2015.january.30.8.
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Tao, C. W. "Genetic polymorphisms of VKORC1, CYP2C9, CYP4F2 in Bai-, Zang-Chinese." Heart 97, Suppl 3 (2011): A112—A113. http://dx.doi.org/10.1136/heartjnl-2011-300867.332.
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Sakiene, Ruta, Alvita Vilkeviciute, Loresa Kriauciuniene, et al. "CYP4F2 (rs2108622) Gene Polymorphism Association with Age-Related Macular Degeneration." Advances in Medicine 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/3917916.
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Background. Age-related macular degeneration is the leading cause of blindness in elderly individuals where aetiology and pathophysiology of age-related macular degeneration are not absolutely clear.Purpose. To determine the frequency of the genotype of rs2108622 in patients with early and exudative age-related macular degeneration.Methods. The study enrolled 190 patients with early age-related macular degeneration, 181 patients with exudative age-related macular degeneration (eAMD), and a random sample of 210 subjects from the general population (control group). The genotyping of rs2108622 was carried out using the real-time polymerase chain reaction method.Results. The analysis of rs2108622 gene polymorphism did not reveal any differences in the distribution of C/C, C/T, and T/T genotypes between the early AMD group, the eAMD group, and the control group. TheCYP4F2(1347C>T)T/Tgenotype was more frequent in males with eAMD compared to females (10.2% versus 0.8%;p=0.0052); alsoT/Tgenotype was less frequently present in eAMD females compared to healthy control females (0.8% versus 6.2%;p=0.027).Conclusion. Rs2108622 gene polymorphism had no predominant effect on the development of early AMD and eAMD. TheT/Tgenotype was more frequent in males with eAMD compared to females and less frequently present in eAMD females compared to healthy females.
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Han, Nayoung, Jung Mi Oh, and In-Wha Kim. "Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans." Journal of Personalized Medicine 11, no. 1 (2021): 33. http://dx.doi.org/10.3390/jpm11010033.
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For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.
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Han, Nayoung, Jung Mi Oh, and In-Wha Kim. "Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans." Journal of Personalized Medicine 11, no. 1 (2021): 33. http://dx.doi.org/10.3390/jpm11010033.
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For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.
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Biss, Tina T., Peter J. Avery, Leonardo R. Brandão, et al. "VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children." Blood 119, no. 3 (2012): 868–73. http://dx.doi.org/10.1182/blood-2011-08-372722.
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Abstract Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (−1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.
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Watanabe, Hiroaki, Satoshi Yamaori, Shinobu Kamijo, Kaori Aikawa, and Shigeru Ohmori. "In Vitro Inhibitory Effects of Sesamin on CYP4F2 Activity." Biological and Pharmaceutical Bulletin 43, no. 4 (2020): 688–92. http://dx.doi.org/10.1248/bpb.b19-00953.
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Zhao, Yanyan, Jingjing Wu, and Guangrei Lai. "EFFECT OF HIGH SALT ON RENAL NKCC2 IN CYP4F2 transgenic mice." Kidney Research and Clinical Practice 31, no. 2 (2012): A88. http://dx.doi.org/10.1016/j.krcp.2012.04.607.
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Kehl, Franz, Liana Cambj-Sapunar, Kristopher G. Maier, et al. "20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat." American Journal of Physiology-Heart and Circulatory Physiology 282, no. 4 (2002): H1556—H1565. http://dx.doi.org/10.1152/ajpheart.00924.2001.
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This study examined the effects of blocking the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) on the acute fall in cerebral blood flow after subarachnoid hemorrhage (SAH) in the rat. In vehicle-treated rats, regional cerebral blood flow (rCBF) measured with laser-Doppler flowmetry fell by 30% 10 min after the injection of 0.3 ml of arterial blood into the cisterna magna, and it remained at this level for 2 h. Pretreatment with inhibitors of the formation of 20-HETE, 17-octadecynoic acid (17-ODYA; 1.5 nmol intrathecally) and N-hydroxy- N′-(4-butyl-2-methylphenyl)formamidine (HET0016; 10 mg/kg iv), reduced the initial fall in rCBF by 40%, and rCBF fully recovered 1 h after induction of SAH. The concentration of 20-HETE in the cerebrospinal fluid rose from 12 ± 2 to 199 ± 17 ng/ml after SAH in vehicle-treated rats. 20-HETE levels averaged only 15 ± 11 and 39 ± 13 ng/ml in rats pretreated with 17-ODYA or HET0016, respectively. HET0016 selectively inhibited the formation of 20-HETE in rat renal microsomes with an IC50of <15 nM and human recombinant CYP4A11, CYP4F2, and CYP4F3 enzymes with an IC50 of 42, 125, and 100 nM, respectively. These results indicate that 20-HETE contributes to the acute fall in rCBF after SAH in rats.
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Marji, Jackleen S., Mong-Heng Wang, and Michal Laniado-Schwartzman. "Cytochrome P-450 4A isoform expression and 20-HETE synthesis in renal preglomerular arteries." American Journal of Physiology-Renal Physiology 283, no. 1 (2002): F60—F67. http://dx.doi.org/10.1152/ajprenal.00265.2001.
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20-Hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictor and mediator of the myogenic response, is a major arachidonic acid metabolite in the microvasculature of the rat kidney formed primarily by the cytochrome P-450 (CYP) 4A isoforms, CYP4A1, CYP4A2, and CYP4A3. We examined CYP4A isoform expression and 20-HETE synthesis in microdissected interlobar, arcuate, and interlobular arteries; mRNA for all CYP4A isoforms was identified by RT-PCR. Western blot analysis indicated that the levels of CYP4A2/4A3-immunoreactive protein increased with decreased arterial diameter, whereas those of CYP4A1-immunoreactive protein remained unchanged. 20-HETE synthesis was the highest in the interlobular arteries (17 ± 1.62 nmol · mg−1 · h−1) and, like CYP4A2/4A3-immunoreactive protein, decreased with increasing vessel diameter (4.5 ± 1.21, 2.65 ± 0.58, and 0.81 ± 0.14 nmol · mg−1 · h−1 in the arcuate, interlobar, and segmental arteries, respectively). 20-HETE synthesis in the renal artery and the abdominal aorta was undetectable. The observed decreased immunoreactivity of NADPH-cytochrome P-450 ( c) oxidoreductase with increased arterial diameter provided a possible explanation for the decreased capacity to generate 20-HETE in the large arteries. The increase in CYP4A isoform expression and 20-HETE synthesis with decreasing diameter along the preglomerular arteries and the potent biological activity of 20-HETE underscore the significance of 20-HETE as a modulator of renal hemodynamics.
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Russo, Anelise, Patrícia M. Biselli-Chicote, Rosa S. Kawasaki-Oyama, et al. "Differential Expression of Prostaglandin I2 Synthase Associated with Arachidonic Acid Pathway in the Oral Squamous Cell Carcinoma." Journal of Oncology 2018 (November 8, 2018): 1–13. http://dx.doi.org/10.1155/2018/6301980.
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Introduction. Differential expression of genes encoding cytochrome P450 (CYP) and other oxygenases enzymes involved in biotransformation mechanisms of endogenous and exogenous compounds can lead to oral tumor development. Objective. We aimed to identify the expression profile of these genes, searching for susceptibility biomarkers in oral squamous cell carcinoma. Patients and Methods. Sixteen oral squamous cell carcinoma samples were included in this study (eight tumor and eight adjacent non-tumor tissues). Gene expression quantification was performed using TaqMan Array Human CYP450 and other Oxygenases 96-well plate (Applied Biosystems) by real time qPCR. Protein quantification was performed by ELISA and IHC methods. Bioinformatics tools were used to find metabolic pathways related to the enzymes encoded by differentially expressed genes. Results. CYP27B1, CYP27A1, CYP2E1, CYP2R1, CYP2J2, CYP2U1, CYP4F12, CYP4X1, CYP4B1, PTGIS, ALOX12, and MAOB genes presented differential expression in the oral tumors. After correction by multiple tests, only the PTGIS (Prostaglandin I2 Synthase) gene presented significant differential expression (P < 0.05). The PTGIS gene and protein were reduced in oral tumors. Conclusion. PTGIS presents downexpression in oral tumors. PTGIS play an important role in the arachidonic acid metabolism. Arachidonic acid and/or metabolites are derived from this pathway, which can influence the regulation of important physiological mechanisms in tumorigenesis process.
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Baturina, Olga, Denis Andreev, Ludmila Fedina, et al. "Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation." Pharmacology 107, no. 3-4 (2022): 216–26. http://dx.doi.org/10.1159/000521531.
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<b><i>Introduction:</i></b> The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12–20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF). <b><i>Methods:</i></b> 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy – high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA). <b><i>Results:</i></b> None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C&#x3e;T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA. <b><i>Conclusion:</i></b> In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C&#x3e;T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.
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Cavieres, Mirta, Marcelo Suárez, Gabriel Verón, Luis Abel Quiñones, and Nelson Miguel Varela. "Análisis farmacogenético retrospectivo de una paciente pediátrica en tratamiento anticoagulante: caso clínico." Biomédica 41, no. 3 (2021): 403–8. http://dx.doi.org/10.7705/biomedica.5840.
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Se presenta el caso clínico de una paciente de 10 años diagnosticada con miocardiopatía dilatada, quien registró valores en el índice internacional normalizado (International Normalized Ratio, INR) superiores a 10 con la dosis estándar de acenocumarol, además de otros valores que indicaban el estado incoagulable, lo que obligó a suspender y reiniciar el tratamiento en varias ocasiones. Después de más de 30 días de tratamiento, sorprendentemente se lograron los niveles esperados y estables en el INR con la mitad de a dosis recomendada para una paciente de su edad y peso.Se decidió hacer un análisis farmacogenético retrospectivo del caso mediante RT-PCR con sondas TaqMan™ que incluyó cinco polimorfismos de un solo nucleótido y distinto grado de asociación con la dosis-respuesta a los fármacos antivitamínicos K (AVK): rs2108622 (gen CYP4F2), rs9923231, rs7294 (gen VKORC1), rs1799853 y rs1057910 (gen CYP2C9). La paciente resultó ser homocigota para el rs9923231 (VKORC1) y heterocigota para el rs2108622 (CYP4F2). Se ha evidenciado a nivel nacional e internacional que este perfil genético está fuertemente asociado con una necesidad de dosis menores de antivitamínicos K.En conclusión, el análisis farmacogenético confirmó que la condición genética de la paciente, la cual conlleva una baja expresión de la enzima VKORC1 (blanco terapéutico de los antivitamínicos K), hacía predecible la necesidad de una dosis menor a la establecida según los protocolos clínicos recomendados por la Food and Drug Administration (FDA) y PharmGKB™ para los fármacos cumarínicos.
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Niedrig, David F., Ali Rahmany, Kai Heib, et al. "Clinical Relevance of a 16-Gene Pharmacogenetic Panel Test for Medication Management in a Cohort of 135 Patients." Journal of Clinical Medicine 10, no. 15 (2021): 3200. http://dx.doi.org/10.3390/jcm10153200.
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There is a growing number of evidence-based indications for pharmacogenetic (PGx) testing. We aimed to evaluate clinical relevance of a 16-gene panel test for PGx-guided pharmacotherapy. In an observational cohort study, we included subjects tested with a PGx panel for variants of ABCB1, COMT, CYP1A2, CYP2B6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, CYP4F2, DPYD, OPRM1, POR, SLCO1B1, TPMT and VKORC1. PGx-guided pharmacotherapy management was supported by the PGx expert system SONOGEN XP. The primary study outcome was PGx-based changes and recommendations regarding current and potential future medication. PGx-testing was triggered by specific drug–gene pairs in 102 subjects, and by screening in 33. Based on PharmGKB expert guidelines we identified at least one “actionable” variant in all 135 (100%) tested patients. Drugs that triggered PGx-testing were clopidogrel in 60, tamoxifen in 15, polypsychopharmacotherapy in 9, opioids in 7, and other in 11 patients. Among those, PGx variants resulted in clinical recommendations to change PGx-triggering drugs in 33 (32.4%), and other current pharmacotherapy in 23 (22.5%). Additional costs of panel vs. single gene tests are moderate, and the efficiency of PGx panel testing challenges traditional cost-benefit calculations for single drug–gene pairs. However, PGx-guided pharmacotherapy requires specialized expert consultations with interdisciplinary collaborations.
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Singh, Onkar, Edwin Sandanaraj, Koilan Subramanian, Lai Heng Lee, and Balram Chowbay. "Influence of CYP4F2 rs2108622 (V433M) on Warfarin Dose Requirement in Asian Patients." Drug Metabolism and Pharmacokinetics 26, no. 2 (2011): 130–36. http://dx.doi.org/10.2133/dmpk.dmpk-10-rg-080.
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Luo, X. H., G. R. Li, and H. Y. Li. "Association of the CYP4F2 rs2108622 genetic polymorphism with hypertension: a meta-analysis." Genetics and Molecular Research 14, no. 4 (2015): 15133–39. http://dx.doi.org/10.4238/2015.november.25.1.
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Kovarik, John M., Kiran Dole, Gilles-Jacques Riviere, et al. "Ketoconazole Increases Fingolimod Blood Levels in a Drug Interaction via CYP4F2 Inhibition." Journal of Clinical Pharmacology 49, no. 2 (2009): 212–18. http://dx.doi.org/10.1177/0091270008329553.
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