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#36318660   2022/11/01 To Up

Discovery of Novel Pyrazolylpyridine Derivatives for 20-Hydroxyeicosatetraenoic Acid Synthase Inhibitors with Selective CYP4A11/4F2 Inhibition.

20-Hydroxyeicosatetraenoic acid (20-HETE) is one of the major oxidized arachidonic acid (AA) metabolites produced by cytochrome P450 (CYP) 4A11 and CYP4F2 isozymes in the human liver and kidney. Numerous studies have suggested the involvement of 20-HETE in the pathogenesis of renal diseases, and suppression of 20-HETE production by inhibition of CYP4A11 and CYP4F2 may be an attractive therapeutic strategy for renal diseases. At first, we identified methylthiazole derivative as a potent dual inhibitor of CYP4A11 and CYP4F2. An optimization study of a series of derivatives with a molecular weight of around 300 to improve aqueous solubility and selectivity against drug-metabolizing CYPs while maintaining the CYP4A11- and CYP4F2-inhibitory activities led to the identification of acetylpiperidine compound . Compound inhibited 20-HETE production in both human and rat renal microsomes and exhibited a favorable pharmacokinetic profile. Furthermore, also significantly inhibited renal 20-HETE production in Sprague-Dawley rats after oral dosing at 0.1 mg/kg.
Madoka Kawamura, Yohei Kobashi, Hiroaki Tanaka, Ayako Bohno-Mikami, Makoto Hamada, Yuji Ito, Takashi Hirata, Hiroki Ohara, Naoki Kojima, Hiroko Koretsune, Emi Gunji, Takuya Fukunaga, Shoko Inatani, Yoshitaka Hasegawa, Akinori Suzuki, Teisuke Takahashi, Hiroyuki Kakinuma

1006 related Products with: Discovery of Novel Pyrazolylpyridine Derivatives for 20-Hydroxyeicosatetraenoic Acid Synthase Inhibitors with Selective CYP4A11/4F2 Inhibition.

1 G 100ul 1 G 1 G 1 G5 Inhibitors 500 G 1 G50ul10 mg 1 G25 g

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#35597366   2022/05/18 To Up

Crosstalk between adenosine receptors and CYP450-derived oxylipins in the modulation of cardiovascular, including coronary reactive hyperemic response.

Adenosine is a ubiquitous endogenous nucleoside or autacoid that affects the cardiovascular system through the activation of four G-protein coupled receptors: adenosine A receptor (AAR), adenosine A receptor (AAR), adenosine A receptor (AAR), and adenosine A receptor (AAR). With the rapid generation of this nucleoside from cellular metabolism and the widespread distribution of its four G-protein coupled receptors in almost all organs and tissues of the body, this autacoid induces multiple physiological as well as pathological effects, not only regulating the cardiovascular system but also the central nervous system, peripheral vascular system, and immune system. Mounting evidence shows the role of CYP450-enzymes in cardiovascular physiology and pathology, and the genetic polymorphisms in CYP450s can increase susceptibility to cardiovascular diseases (CVDs). One of the most important physiological roles of CYP450-epoxygenases (CYP450-2C & CYP2J2) is the metabolism of arachidonic acid (AA) and linoleic acid (LA) into epoxyeicosatrienoic acids (EETs) and epoxyoctadecaenoic acid (EpOMEs) which generally involve in vasodilation. Like an increase in coronary reactive hyperemia (CRH), an increase in anti-inflammation, and cardioprotective effects. Moreover, the genetic polymorphisms in CYP450-epoxygenases will change the beneficial cardiovascular effects of metabolites or oxylipins into detrimental effects. The soluble epoxide hydrolase (sEH) is another crucial enzyme ubiquitously expressed in all living organisms and almost all organs and tissues. However, in contrast to CYP450-epoxygenases, sEH converts EETs into dihydroxyeicosatrienoic acid (DHETs), EpOMEs into dihydroxyoctadecaenoic acid (DiHOMEs), and others and reverses the beneficial effects of epoxy-fatty acids leading to vasoconstriction, reducing CRH, increase in pro-inflammation, increase in pro-thrombotic and become less cardioprotective. Therefore, polymorphisms in the sEH gene (Ephx2) cause the enzyme to become overactive, making it more vulnerable to CVDs, including hypertension. Besides the sEH, ω-hydroxylases (CYP450-4A11 & CYP450-4F2) derived metabolites from AA, ω terminal-hydroxyeicosatetraenoic acids (19-, 20-HETE), lipoxygenase-derived mid-chain hydroxyeicosatetraenoic acids (5-, 11-, 12-, 15-HETEs), and the cyclooxygenase-derived prostanoids (prostaglandins: PGD, PGF; thromboxane: Txs, oxylipins) are involved in vasoconstriction, hypertension, reduction in CRH, pro-inflammation and cardiac toxicity. Interestingly, the interactions of adenosine receptors (AAR, AAR) with CYP450-epoxygenases, ω-hydroxylases, sEH, and their derived metabolites or oxygenated polyunsaturated fatty acids (PUFAs or oxylipins) is shown in the regulation of the cardiovascular functions. In addition, much evidence demonstrates polymorphisms in CYP450-epoxygenases, ω-hydroxylases, and sEH genes (Ephx2) and adenosine receptor genes (ADORA1 & ADORA2) in the human population with the susceptibility to CVDs, including hypertension. CVDs are the number one cause of death globally, coronary artery disease (CAD) was the leading cause of death in the US in 2019, and hypertension is one of the most potent causes of CVDs. This review summarizes the articles related to the crosstalk between adenosine receptors and CYP450-derived oxylipins in vascular, including the CRH response in regular salt-diet fed and high salt-diet fed mice with the correlation of heart perfusate/plasma oxylipins. By using AAR, AAR, eNOS sEH or Ephx2, vascular sEH-overexpressed (Tie2-sEH Tr), vascular CYP2J2-overexpressed (Tie2-CYP2J2 Tr), and wild-type (WT) mice. This review article also summarizes the role of pro-and anti-inflammatory oxylipins in cardiovascular function/dysfunction in mice and humans. Therefore, more studies are needed better to understand the crosstalk between the adenosine receptors and eicosanoids to develop diagnostic and therapeutic tools by using plasma oxylipins profiles in CVDs, including hypertensive cases in the future.
Mohammed A Nayeem, Ahmad Hanif, Werner J Geldenhuys, Stephanie Agba

2013 related Products with: Crosstalk between adenosine receptors and CYP450-derived oxylipins in the modulation of cardiovascular, including coronary reactive hyperemic response.



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#35204686   2022/01/22 To Up

Exploring the Interactome of Cytochrome P450 2E1 in Human Liver Microsomes with Chemical Crosslinking Mass Spectrometry.

Aiming to elucidate the system-wide effects of the alcohol-induced increase in the content of cytochrome P450 2E1 (CYP2E1) on drug metabolism, we explored the array of its protein-protein interactions (interactome) in human liver microsomes (HLM) with chemical crosslinking mass spectrometry (CXMS). Our strategy employs membrane incorporation of purified CYP2E1 modified with photoreactive crosslinkers benzophenone-4-maleimide and 4-(-succinimidylcarboxy)benzophenone. Exposure of bait-incorporated HLM samples to light was followed by isolating the His-tagged bait protein and its crosslinked aggregates on Ni-NTA agarose. Analyzing the individual bands of SDS-PAGE slabs of thereby isolated protein with the toolset of untargeted proteomics, we detected the crosslinked dimeric and trimeric complexes of CYP2E1 with other drug-metabolizing enzymes. Among the most extensively crosslinked partners of CYP2E1 are the cytochromes P450 2A6, 2C8, 3A4, 4A11, and 4F2, UDP-glucuronosyltransferases (UGTs) 1A and 2B, fatty aldehyde dehydrogenase (ALDH3A2), epoxide hydrolase 1 (EPHX1), disulfide oxidase 1α (ERO1L), and ribophorin II (RPN2). These results demonstrate the exploratory power of the proposed CXMS strategy and corroborate the concept of tight functional integration in the human drug-metabolizing ensemble through protein-protein interactions of the constituting enzymes.
Dmitri R Davydov, Bikash Dangi, Guihua Yue, Deepak S Ahire, Bhagwat Prasad, Victor G Zgoda

1543 related Products with: Exploring the Interactome of Cytochrome P450 2E1 in Human Liver Microsomes with Chemical Crosslinking Mass Spectrometry.

96T 100ul100 μg100 units2ug100 μg100 μg5 100 μg100 μg

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#35195639   2022/03/09 To Up

Ultrafast dissociation of ammonia: Auger Doppler effect and redistribution of the internal energy.

We study vibrationally-resolved resonant Auger (RAS) spectra of ammonia recorded in coincidence with the NH fragment, which is produced in the course of dissociation either in the core-excited 1s4a11 intermediate state or the first spectator 3a4a11 final state. Correlation of the NH ion flight times with electron kinetic energies allows directly observing the Auger-Doppler dispersion for each vibrational state of the fragment. The median distribution of the kinetic energy release , derived from the coincidence data, shows three distinct branches as a function of Auger electron kinetic energy : + 1.75 = const for the molecular band; = const for the fragment band; and + = const for the region preceding the fragment band. The deviation of the molecular band dispersion from + = const is attributed to the redistribution of the available energy to the dissociation energy and excitation of the internal degrees of freedom in the molecular fragment. We found that for each vibrational line the dispersive behavior of is very sensitive to the instrumental uncertainty in the determination of causing the competition between the Raman ( + = const) and Auger ( = const) dispersions: increase in the broadening of the finite kinetic energy release resolution leads to a change of the dispersion from the Raman to the Auger one.
Oksana Travnikova, Edwin Kukk, Farzad Hosseini, Sari Granroth, Eero Itälä, Tatiana Marchenko, Renaud Guillemin, Iyas Ismail, Roba Moussaoui, Loïc Journel, John Bozek, Ralph Püttner, Pavel Krasnov, Victor Kimberg, Faris Gel'mukhanov, Maria Novella Piancastelli, Marc Simon

2097 related Products with: Ultrafast dissociation of ammonia: Auger Doppler effect and redistribution of the internal energy.

5 G100 μg100 μg1000 tests100 μg100 μg100 μg100 μg100ug100 μg100 μg100 μg

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#34785671   2021/11/16 To Up

Dramatic activation of an antibody by a single amino acid change in framework.

Antibody function is typically entirely dictated by the Complementarity Determining Regions (CDRs) that directly bind to the antigen, while the framework region acts as a scaffold for the CDRs and maintains overall structure of the variable domain. We recently reported that the rabbit monoclonal antibody 4A11 (rbt4A11) disrupts signaling through both TGFβ2 and TGFβ3 (Sun et al. in Sci Transl Med, 2021. https://doi.org/10.1126/scitranslmed.abe0407 ). Here, we report a dramatic, unexpected discovery during the humanization of rbt4A11 where, two variants of humanized 4A11 (h4A11), v2 and v7 had identical CDRs, maintained high affinity binding to TGFβ2/3, yet exhibited distinct differences in activity. While h4A11.v7 completely inhibited TGFβ2/3 signaling like rbt4A11, h4A11.v2 did not. We solved crystal structures of TGFβ2 complexed with Fab fragments of h4A11.v2 or h4A11.v7 and identified a novel interaction between the two heavy chain molecules in the 2:2 TGFb2:h4A11.v2-Fab complex. Further characterization revealed that framework residue variations at either position 19, 79 or 81 (Kabat numbering) of the heavy chain strikingly converts h4A11.v2 into an inhibitory antibody. Our work suggests that in addition to CDRs, framework residues and interactions between Fabs in an antibody could be engineered to further modulate activity of antibodies.
Wei-Ching Liang, Jianping Yin, Patrick Lupardus, Jianhuan Zhang, Kelly M Loyet, Jawahar Sudhamsu, Yan Wu

2594 related Products with: Dramatic activation of an antibody by a single amino acid change in framework.

100ug Lyophilized100 μg100ug Lyophilized100ug Lyophilized100μg100ug Lyophilized100ug100μg100ug Lyophilized100ug100 ug

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#34330716   2021/07/30 To Up

Cytochrome Binds Tightly to Several Human Cytochrome P450 Enzymes.

Numerous studies have been reported in the past 50-plus years regarding the stimulatory role of cytochrome ( ) in some, but not all, microsomal cytochrome P450 (P450) reactions with drugs and steroids. A missing element in most of these studies has been a sensitive and accurate measure of binding affinities of with P450s. In the course of work with P450 17A1, we developed a fluorescent derivative of a human site-directed mutant, Alexa 488-T70C- , that could be used in binding assays at sub-μM concentrations. Alexa 488-T70C- bound to human P450s 1A2, 2B6, 2C8, 2C9, 2E1, 2S1, 4A11, 3A4, and 17A1, with estimated values ranging from 2.5 to 61 nM. Only weak binding was detected with P450 2D6, and no fluorescence attenuation was observed with P450 2A6. All of the P450s that bound have some reported activity stimulation except for P450 2S1. The affinity of P450 3A4 for was decreased somewhat by the presence of a substrate or inhibitor. The fluorescence of a P450 3A4•Alexa 488-T70C- complex was partially restored by titration with NADPH-P450 reductase (POR) ( 89 nM), suggesting the existence of a ternary P450 3A4- -POR complex, as observed previously with P450 17A1. Gel filtration evidence was also obtained for this ternary complex with P450 3A4. Overall, the results indicated that the affinity of for many P450s is very high, and that ternary P450- -POR complexes are relevant in P450 3A4 reactions as opposed to a shuttle mechanism. SIGNIFICANCE STATEMENT: High-affinity binding of cytochrome ( ) ( < 100 nM) was observed with many drug-metabolizing cytochrome P450 (P450) enzymes. There is some correlation of binding with reported stimulation, with several exceptions. Evidence is provided for a ternary P450 3A4- -NADPH-P450 reductase complex.
Donghak Kim, Vitchan Kim, Yasuhiro Tateishi, F Peter Guengerich

1092 related Products with: Cytochrome Binds Tightly to Several Human Cytochrome P450 Enzymes.

96T 100ul50 ug 100ul 100ul100 µg250ul 100ul0.1 mg

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#33350342   2020/12/28 To Up

Expression of cytochrome P450 isozyme transcripts and activities in human livers.

Individual differences in cytochrome P450 (CYP) enzymes contribute to responses to drugs and environmental chemicals. The expression of CYPs is influenced by sex, age, and ethnicity. Human CYP studies are often conducted with human liver microsomes and liver cells to evaluate chemical induction and drug interactions. However, the basal or constitutive expression of CYP transcripts and enzyme activities in the intact liver are also important in our understanding of individual variation in CYPs. This study utilised 100 human liver samples to profile the constitutive expression of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 4A11 enzyme activity and transcript levels. The mRNA expression of the CYPs and xenobiotic receptors , , and was examined qPCR. Results showed that there was greater inter-individual variation in mRNA expression than in enzyme activities, except for CYP2C19. Females had higher CYP3A4 activity than males. Children had lower CYP4A14 activity, while elderly had lower P450 oxidoreductase activity. Compared to Caucasians, Hispanics had higher CYP2C8 activity and higher , , and mRNA expression, whereas African Americans had lower CYP2D6 mRNA expression. These results add to our understanding of individual variations in xenobiotic metabolism and toxicology.
Jie Liu, Yuan-Fu Lu, J Christopher Corton, Curtis D Klaassen

2099 related Products with: Expression of cytochrome P450 isozyme transcripts and activities in human livers.

96T96T 100ul100 μg500 100 μg0.1 ml100 μg100 μg100 μg2 100 μg

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#33125290   2020/11/16 To Up

Human mass balance, metabolism, and cytochrome P450 phenotyping of lusutrombopag.

The human mass balance of lusutrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, was characterised in seven healthy male subjects after a single oral dose of [C]-lusutrombopag (2 mg, 100 μCi) in solution. Lusutrombopag was the main component in plasma, accounting for 56% of plasma radioactivity AUC. In plasma, the half-life of radioactivity (70.7 h) was longer than that of lusutrombopag (25.7 h), suggesting the presence of long circulating metabolites. The main excretion pathway of lusutorombopag was feces, with a radioactivity recovery of approximately 83% within 336 h post-dose. M6 (lusutrombopag--propanol or lusutrombopag--acetic acid) and M7 (lusutrombopag--ethane-1,2-diol) were also identified as main components in feces, accounting for at most 17.9%, and 16.9% of the dose, respectively, and were β-oxidation related metabolites. Our metabolism study of lusutrombopag indicated that β-oxidation was a subsequent metabolism of ω-oxidation and CYP4 enzymes, including CYP4A11, were the major isozymes contributing to ω-oxidation. In conclusion, lusutrombopag is primarily eliminated via ω-oxidation and excreted in the feces, where CYP4 enzymes play an important role.
Tomoyuki Kawachi, Mizuki Ninomiya, Takayuki Katsube, Toshihiro Wajima, Takushi Kanazu

2697 related Products with: Human mass balance, metabolism, and cytochrome P450 phenotyping of lusutrombopag.

100ul96T96T1000 1-8 Sample Kit0.1 mg32-50 Sample Kit 100ul200 16-22 Sample Kit50 ug 100ul

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#32124935   2020/01/28 To Up

CYP4A11 is involved in the development of nonalcoholic fatty liver disease via ROS‑induced lipid peroxidation and inflammation.

Nonalcoholic fatty liver disease (NAFLD) is a fat metabolism disorder that occurs in liver cells. The development of NAFLD is considered to be associated with hepatic oxidative stress. The present study aimed to investigate the role of cytochrome P450 4A11 (CYP4A11) in the pathogenesis of NAFLD. The levels of plasma CYP4A11 and lipid peroxidation products levels exhibited a high correlation, and were increased significantly compared with those from normal subjects. Further in vitro studies demonstrated that the expression levels of CYP4A11 and the content of reactive oxygen species (ROS) were increased in free fatty acid (FFA)‑stimulated HepG2 cells. Clofibrate, a CYP4A11 inducer, aggravated cell damage. Opposite results were observed for the CYP4A11 inhibitor HET0016, which attenuated apoptosis in FFA‑treated cells. Furthermore, CYP4A11 gene overexpression and silencing were used to investigate the effects on inflammatory cytokine secretion. The data demonstrated that CYP4A11 promoted an increase in the mRNA expression of tumor necrosis factor α, interleukin (IL)‑1β and IL‑6 in response to FFA. In addition, western blot analysis highlighted that CYP4A11 caused an upregulation of phosphorylated p65 levels and therefore affected the NF‑κB signaling pathway. The data demonstrated that CYP4A11 may metabolize fatty acids to promote the production of ROS and accelerate the progression of NAFLD.
Huifang Gao, Yaru Cao, Hongguang Xia, Xiangyu Zhu, Yong Jin

2713 related Products with: CYP4A11 is involved in the development of nonalcoholic fatty liver disease via ROS‑induced lipid peroxidation and inflammation.

50 ulN/A 50 UG0.1ml (1mg/ml)100 ulN/A 100 ul50 ul

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#32047554   2020/01/14 To Up

Alteration of CYP4A11 expression in renal cell carcinoma: diagnostic and prognostic implications.

: Cytochrome P-450 4A11 (CYP4A11) and peroxisome proliferator-activated receptor-α (PPARα) are expressed at high levels in renal proximal tubules, and upregulation of CYP4A11 protein levels is known to be influenced by PPAR agonists. The goal of this study was to evaluate the clinicopathological role of CYP4A11 expression in renal cell carcinoma (RCC). : We performed immunohistochemical analysis of CYP4A11, CYP4A22 and PPARα and correlated the results with the clinicopathological features of RCC (n=139). Reverse transcription digital droplet polymerase chain reaction (RT-ddPCR) against CYP4A11 and CYP4A22 was also performed. : CYP4A11 mRNA expression levels were higher in non-neoplastic kidney tissues than in matched tumor tissues in 12 matched pairs of freshly frozen primary clear-cell RCC (ccRCC) and nontumor tissue (p=0.002). Immunohistochemical staining showed that CYP4A11 expression was significantly lower in ccRCC than in non-ccRCCs, including papillary, chromophobe, and unclassified RCCs (p<0.001). CYP4A11 expression was associated with PPARα expression, males and high nuclear histologic grades (p=0.001, p=0.018 and p<0.001). Univariate and multivariate analyses revealed that CYP4A11 expression was correlated with short overall survival (p=0.007 and p=0.010). : These findings suggest that CYP4A11 expression is a potential poor prognostic factor of RCC. The considerable decrease in CYP4A11 expression is a predictive diagnostic factor of ccRCC, and CYP4A11 metabolism in ccRCC might be different from that in non-ccRCCs.
Sup Kim, Jin Man Kim, Hyo Jin Lee, Jae Sung Lim, In-Ock Seong, Kyung-Hee Kim

2414 related Products with: Alteration of CYP4A11 expression in renal cell carcinoma: diagnostic and prognostic implications.



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