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Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
Changes in the renal 20-HETE and EET levels have been noted in many hypertensive models, and drugs targeting these pathways have been shown to influence pathogenesis of RVD in preclinical studies. In RVD, there is enhanced angiotensin II activity due to activation of the renin-angiotensin system, and this results in elevated 20-HETE and decreased EET levels. These contribute to extracellular matrix deposition, increased endothelin release, vascular remodeling, vasoconstriction, and enhanced glomerulosclerosis and atherogenesis (Kim and Iwao, 2000). For example, in mice with induced renovascular hypertension, sEH inhibition restored the role of EETs in endothelium-dependent relaxation, and eventually attenuated increased blood pressure, cardiac hypertrophy and coronary endothelial dysfunction (Gao et al., 2011). In recent years, allelic polymorphisms in CYP4A11 and CYP4F2 and sEHs have been associated with altered 20-HETE levels and variations in blood pressure in rodent models as well as human studies (Capdevila and Wang, 2013; Ward et al., 2014). More specifically, a nucleotide change (T to C) at position 8590 in the human CYP4A11 that reduces 20-HETE formation has been linked to the development of hypertension due to loss of 20-HETE-mediated natriuresis (Laffer et al., 2008). The G421C polymorphism in the CYP4F2 in Chinese subjects has additionally been linked to hypertension (Liu et al., 2006b).
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Mice have nine CYP4f genes and humans have six CYP4F g enes encoding CYP4F2, 4F3, 4F8, 4F11, 4F12, and 4F22. The CYP4F gene family is clustered in a 0.5-Mb stretch of genomic DNA on the p13 region of chromosome 19 (Kirischian and Wilson 2012). CYP4F2 and 4F3B have 93% amino acid sequence identity and both share a high degree of identity with other CYP4F enzymes. CYP4F enzymes account for 15% of the total hepatic CYPs (Michaels and Wang 2014). Members of the CYP4F subfamily are important enzymes involved in the biotransforma-tion of endogenous eicosanoids (e.g., AA, PGs, and LTB4) and are involved in the regulation of many physiological functions, such as inflammation and vasoconstriction (Fer et al. 2008; Hardwick 2008; Kikuta et al. 1998, 2004, 2007). CYP4F2 is the principal hepatic ω-hydroxylase for LTB4 and AA, resulting in deactivation of LTB4 and formation of the potent vasoconstrictor 20-HETE, respectively (Jin et al. 1998; Powell et al. 1998). Both CYP4F3A and 4F3B catalyze the ω-hydroxylation of LTB4 and AA; however, CYP4F3A has 30-fold greater affinity (Km) for LTB4 and conversely 8.4-fold lower affinity for AA than 4F3B (Christmas et al. 2001). As ω-hydroxylases, CYP4Fs have the potential to convert AA to 20-HETE that has potent actions on renal tubular and vascular functions (Hardwick 2008; Kikuta et al. 2007). The ω-hydroxylated LTB4 undergoes further metabolism to 20-carboxy-LTB4, which can undergo B-oxidation from its ω-side along with traditional ß-oxidation from the C1 carbon, leading to the inactivation of this potent proinflammatory agent.
Genotype-Guided vs Clinically-Guided Stable Warfarin Dose Prediction and Stable Dose Establishment In A Predominantly Non-European Ancestry Population
Published in Expert Review of Precision Medicine and Drug Development, 2021
Annesti F. Elmasri, Heejin Hur, Jin Han, James C. Lee
The U.S. Food and Drug Administration currently suggests incorporating CYP2C9 and VKORC1 genotypes to guide warfarin dosing when results are available [3]. Guidelines published by the Clinical Pharmacogenetics Implementation Consortium suggest that individuals who are known carriers of CYP2C9, VKORC1, CYP4F2, and the CYP2C cluster variant alleles are likely to express altered warfarin metabolism and warfarin sensitivity which require lower warfarin dose requirements[2]. Depending on the variant present, INR response may be extended or respond rapidly following dose changes. Dosing algorithms incorporating pharmacogenetic test results, in addition to drug‐drug interactions, age, weight, height, race, and ancestry, are available to help guide users, however, they do not incorporate degree of dietary vitamin K intake [4]. Previous published data have suggested genotype‐guided warfarin dosing can improve anticoagulation‐related clinical outcomes and has been associated with improved percentage of INR time in therapeutic range from the time of warfarin initiation as well as improved combined risk reduction of major bleeding, supratherapeutic INRs of 4 or greater, or death, but that the benefit of genetically‐guided warfarin therapy may vary for non‐European ancestral groups [5,6,11].
Human mass balance, metabolism, and cytochrome P450 phenotyping of lusutrombopag
Published in Xenobiotica, 2021
Tomoyuki Kawachi, Mizuki Ninomiya, Takayuki Katsube, Toshihiro Wajima, Takushi Kanazu
[14C]-lusutrombopag (Figure 1) was synthesised by Shionogi & Co., Ltd. (Osaka, Japan) with the specific activity of 1.95 MBq/mg and radiochemical purity of 96%. Reference standard for lusutrombopag and its metabolites were synthesised and obtained from Shionogi & Co., Ltd., Japan: M1 (lusutrombopag acyl glucuronide), M2 (taurine conjugate of lusutrombopag β-oxidated carboxylic acid), M3 (lusutrombopag-5-keto), M4 (lusutrombopag β-oxidated carboxylic acid), and M5 (lusutrombopag-O-deshexyl). Internal standards d13-lusutrombopag, d11-M3, and fluoro-substituted-M5 were also supplied by Shionogi & Co., Ltd. Recombinant human cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9*1, CYP2C19, CYP2D6*1, CYP3A4, CYP4A11, and CYP4F2) were purchased from BD Biosciences (Franklin Lakes, NJ). Pooled Human liver microsomes and cryopreserved human hepatocytes were purchased from Sekisui XenoTech, LLC (Kansas City, KS). Nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) was purchased from ORIENTAL YEAST CO., LTD (Tokyo, Japan). All other reagents were of high-performance liquid chromatography (HPLC) or guaranteed.
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
‘Active’ vitamin K is oxidatively converted into an ‘inactive’ form and subsequently re-activated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin competitively inhibits subunit 1 of multi-unit VKOR complex, thus depleting functional vitamin K reserves and hence reducing synthesis of active clotting factors. Its antithrombogenic effects generally occur only after functional coagulation factors IX and X are diminished (usually 2–7 days following initiation of therapy), with no effect on catabolism of blood coagulation factors. This anticoagulant inhibits thrombus formation when stasis is induced and prevents extension of existing thrombi, with no direct effect on established thrombi. Warfarin prolongs PT and APTT, and phytonadione (vitamin K1) reverses its anticoagulant effect. Warfarin is a substrate of CALU, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP3A4/5, CYP4F2, EPHX1 and GGCX, an inhibitor of CYP2C9, CYP2C19 and VKORC1, and an inducer of CYP2C9, and is transported by ABCB1 [8, 9]. CYP2C9 and VKORC1 variants are determinant in warfarin efficacy and safety.