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See-Hyoung Park, Nguyen Minh Phuc, Jongsung Lee, Zhexue Wu, Jieun Kim, Hyunkyoung Kim, Nam Doo Kim, Taeho Lee, Kyung-Sik Song, Kwang-Hyeon Liu
BACKGROUND: Acetylshikonin is one of the biologically active compounds derived from the root of Lithospermum erythrorhizon, a medicinal plant with anti-cancer and anti-inflammation activity. Although there have been a few previous reports demonstrating that acetylshikonin exerts anti-cancer activity in vitro and in vivo, it is still not clear what is the exact molecular target protein of acetylshikonin in cancer cells. PURPOSE: The purpose of this study is to evaluate the inhibitory effect of acetylshikonin against CYP2J2 enzyme which is predominantly expressed in human tumor tissues and carcinoma cell lines...
January 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Jiaqi Mi, Manman Zhao, Shu Yang, Yufei Jia, Yan Wang, Baolian Wang, Jing Jin, Xiaojian Wang, Qiong Xiao, Jinping Hu, Yan Li
Syl930 is a novel sphingosine-1-phosphate receptor subtype 1 (S1PR1) agonist for the treatment of autoimmune encephalitis with promising receptor selectivity and little risk of bradycardia. Syl930 could be reversibly converted to its phosphorylated metabolite, acting as the active form to provide therapeutic effects, but eliminated principally in the form of oxidative metabolites. The aim of the present study was to identify the cytochrome P450 isoforms (CYPs) responsible for the oxidative metabolism of Syl930...
July 14, 2016: Drug Metabolism and Pharmacokinetics
Eleanor Jing Yi Cheong, Janice Jia Ni Goh, Yanjun Hong, Gopalakrishnan Venkatesan, Yuanjie Liu, Gigi Ngar Chee Chiu, Pipin Kojodjojo, Eric Chun Yong Chan
Rivaroxaban, a direct Factor Xa inhibitor, is indicated for stroke prevention in non-valvular atrial fibrillation (AF). Studies have revealed that the clearance of rivaroxaban is largely attributed to CYP3A4, CYP2J2 metabolism and P-gp efflux pathways. Amiodarone and dronedarone are anti-arrhythmic agents employed in AF management. Amiodarone, dronedarone and their major metabolites, N-desethylamiodarone (NDEA) and N-desbutyldronedarone (NDBD) demonstrate inhibitory effects on CYP3A4 and CYP2J2 with FDA recommended probe substrates...
January 4, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Donghong Zhang, Jinli Lou, Xu Zhang, Lin Zhang, Fei Wang, Danfei Xu, Na Niu, Yidong Wang, Yue Wu, Wei Cui
Hyperhomocysteinemia (HHcy) can result from liver disease or dysfunction and further alters intracellular lipid metabolism. Cytochrome P450 (CYP) arachidonic acid epoxygenases are expressed in human cancers and promote cancer metastasis. This study explored the interaction of Hcy and CYP450 metabolism in hepatocellular carcinoma (HCC). The levels of 4-epoxyeicosatrienoic acid (EET) isomers and their generative enzyme CYP2J2 level as well as intracellular Hcy level were higher in 42 cases of HCC than in paired non-tumor tissue...
December 24, 2016: Oncotarget
Rui Li, Yuan Zhang, Huacheng Yan, Hua Xiao, Yunjun Ruan, Jian Qiu, Lei Shi
Atherosclerosis (AS) is a common pathological basis for the development of various cardiovascular and cerebrovascular diseases, however, currently, no effective treatment against AS has been established. It has previously been suggested that intravascular cytochrome P450 (CYP) oxidase is involved in the pathogenesis of AS. The present study investigated the role of cytochrome P450, family 2, subfamily J, polypeptide 2 (CYP2J2), the most common subtype of CYP oxidase in the human body, in the occurrence and development of AS...
February 2017: Molecular Medicine Reports
William R Arnold, Javier L Baylon, Emad Tajkhorshid, Aditi Das
Cytochrome P450 (CYP) 2J2 is the primary epoxygenase in the heart and is responsible for the epoxidation of arachidonic acid (AA), an ω-6 polyunsaturated fatty acid (PUFA), into anti-inflammatory epoxide metabolites. It also epoxidizes other PUFAs such as docosahexaenoic acid (DHA), linoleic acid (LA), and eicosapentaenoic acid (EPA). Herein, we have performed detailed thermodynamic and kinetic analyses to determine how DHA, LA, and EPA modulate the metabolism of AA by CYP2J2. We use the Nanodisc system to stabilize CYP2J2 and its redox partner, CYP reductase (CPR)...
December 20, 2016: Biochemistry
G Proietti, K K Abelak, D Bishop-Bailey, A Macchiarulo, I Nobeli
An experimentally determined structure for human CYP2J2-a member of the cytochrome P450 family with significant and diverse roles across a number of tissues-does not yet exist. Our understanding of how CYP2J2 accommodates its cognate substrates and how it might be inhibited by other ligands thus relies on our ability to computationally predict such interactions using modelling techniques. In this study we present a computational investigation of the binding of arachidonic acid (AA) to CYP2J2 using homology modelling, induced fit docking (IFD) and molecular dynamics (MD) simulations...
November 2016: Journal of Molecular Modeling
Marco Sisignano, Carlo Angioni, Chul-Kyu Park, Sascha Meyer Dos Santos, Holger Jordan, Maria Kuzikov, Di Liu, Sebastian Zinn, Stephan W Hohman, Yannick Schreiber, Béla Zimmer, Mike Schmidt, Ruirui Lu, Jing Suo, Dong-Dong Zhang, Stephan M G Schäfer, Martine Hofmann, Ajay S Yekkirala, Natasja de Bruin, Michael J Parnham, Clifford J Woolf, Ru-Rong Ji, Klaus Scholich, Gerd Geisslinger
Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sarah E Allison, Yongjuan Chen, Nenad Petrovic, Stefanie Zimmermann, Bjoern Moosmann, Mirko Jansch, Pei H Cui, Colin R Dunstan, Peter I Mackenzie, Michael Murray
Secondary metastases are the leading cause of mortality in patients with breast cancer. Cytochrome P450 (CYP) 2J2 (CYP2J2) is upregulated in many human tumors and generates epoxyeicosanoids from arachidonic acid that promote tumorigenesis and metastasis, but at present there is little information on the genes that mediate these actions. In this study MDA-MB-468 breast cancer cells were stably transfected with CYP2J2 (MDA-2J2 cells) and Affymetrix microarray profiling was undertaken. We identified 182 genes that were differentially expressed in MDA-2J2 cells relative to control (MDA-CTL) cells (log[fold of control] ≥2)...
October 5, 2016: International Journal of Biochemistry & Cell Biology
Katerina Cizkova, Jana Steigerova, Jan Gursky, Jiri Ehrmann
BACKGROUND: Fibrates are widely used hypolipidemic drugs, which serve as ligand of peroxisome proliferator-activated receptor α (PPARα). Recently, they have also been considered as potential anticancer agents. We studied effect of fibrates treatment on cell proliferation, expression of CYP2J2 and concomitant changes in expression of cell cycle regulatory proteins in three different human cell lines: HEK293, HepG2, and HT-29. METHODS: We used WST-1 viability test, western blot and immunocytochemistry for detection of proteins of interests and analysis of cell cycle...
2016: Lipids in Health and Disease
Yunxia Zhao, Ye Hou, Fei Liu, An Liu, Lu Jing, Changzhi Zhao, Yu Luan, Yuanxin Miao, Shuhong Zhao, Xinyun Li
Feed efficiency (FE) is essential for pig production. In this study, 300 significantly differentially expressed (DE) transcripts, including 232 annotated genes, 28 cis- natural antisense transcripts (cis-NATs), and 40 lncRNAs, were identified between the liver of Yorkshire pigs with extremely high and low FE. Among these transcripts, 25 DE lncRNAs were significantly correlated with 125 DE annotated genes at a transcriptional level. These DE genes were primarily enriched in Vitamin A (VA), fatty acid, and steroid hormone metabolism...
September 15, 2016: G3: Genes—Genomes—Genetics
Chi Zhou, Jin Huang, Junxiong Chen, Jinsheng Lai, Fasheng Zhu, Xizhen Xu, Dao Wen Wang
BACKGROUND: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids (AA) to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the treatment of cardiovascular diseases, but little is known about its role on adventitial remodeling. METHODS: We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts (AFs) in vitro treated with Angiotensin II to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling...
2016: Cellular Physiology and Biochemistry
Bei Wang, Hesong Zeng, Zheng Wen, Chen Chen, Dao Wen Wang
Cytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5'-AMP-activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1...
October 2016: Aging Cell
Shuang Geng, Yutong Wang, Yongmei Sun, Jinfeng Li, Honglei Yin, Zhilei Zeng, Xiaopeng Yang, Yuzhen Zhang, Yunliang Wang
AIMS: To investigate the impact of PPAR -γ and CYP2J2 gene single nucleotide polymorphisms (SNPs) and gene- gene interactions on late-onset Alzheimer's disease (LOAD) risk in Chinese Han population. METHODS: A total of 880 participants (514 males, 366 females), with a mean age of 81.7±15.9years old are selected, including 430 LOAD patients and 450 normal participants. Generalized multifactor dimensionality reduction (GMDR) is used to examine interaction among six SNPs, odds ratio (OR) and 95% confident interval (95%CI) are calculated by Logistic regression model...
July 7, 2016: Behavioural Brain Research
Michael Murray
Polyunsaturated fatty acids (PUFAs) undergo cytochrome P450 (CYP)-dependent oxidation to epoxides that modulate important physiological functions, including vasoactivity, inflammation, nociception, proliferation and viability. One of the most important human CYP epoxygenases is human CYP2J2 that is widely expressed in tissues, especially heart, vascular smooth muscle, salivary glands and placenta. Recent studies have shown that overexpression of CYP2J2 in vivo reverses several pathological processes in animals, including hypertension and other cardiovascular pathologies and insulin resistance...
August 2016: Drug Metabolism Reviews
Nicholas I Mundy, Jessica Stapley, Clair Bennison, Rachel Tucker, Hanlu Twyman, Kang-Wook Kim, Terry Burke, Tim R Birkhead, Staffan Andersson, Jon Slate
Bright-red colors in vertebrates are commonly involved in sexual, social, and interspecific signaling [1-8] and are largely produced by ketocarotenoid pigments. In land birds, ketocarotenoids such as astaxanthin are usually metabolically derived via ketolation of dietary yellow carotenoids [9, 10]. However, the molecular basis of this gene-environment mechanism has remained obscure. Here we use the yellowbeak mutation in the zebra finch (Taeniopygia guttata) to investigate the genetic basis of red coloration...
June 6, 2016: Current Biology: CB
Lukasz Przybyl, Nadine Haase, Michaela Golic, Julianna Rugor, Maria Emilia Solano, Petra Clara Arck, Martin Gauster, Berthold Huppertz, Christoph Emontzpohl, Christian Stoppe, Jürgen Bernhagen, Lin Leng, Richard Bucala, Herbert Schulz, Arnd Heuser, M Susanne Weedon-Fekjær, Guro M Johnsen, Dirk Peetz, Friedrich C Luft, Anne Cathrine Staff, Dominik N Müller, Ralf Dechend, Florian Herse
RATIONALE: We hypothesized that cluster of differentiation 74 (CD74) downregulation on placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia. OBJECTIVE: Preeclamptic pregnancies feature hypertension, proteinuria, and placental anomalies. Feto-placental macrophages regulate villous trophoblast differentiation during placental development. Disturbance of this well-balanced regulation can lead to pathological pregnancies...
June 24, 2016: Circulation Research
Francesco Dalle Vedove, Cristiano Fava, Houli Jiang, Giovanni Zanconato, John Quilley, Matteo Brunelli, Valeria Guglielmi, Gaetano Vattemi, Pietro Minuz
BACKGROUND: Epoxyeicosatrienoic acids (EETs) derived from cytochrome P450 (CYP)-dependent metabolism of arachidonic acid are increased in the plasma of women with preeclampsia as compared with normal pregnancy and are significantly higher in fetal than in maternal plasma and erythrocytes. We hypothesized that differences in EET synthesis or metabolism in the feto-placental unit contributed to the observed differences in circulating EETs. METHOD: To evaluate EETs, formation as well as the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), biopsies of placenta were collected from 19 normal pregnancy and 10 preeclampsia at the time of cesarean section delivery...
July 2016: Journal of Hypertension
Vyvyca J Walker, Alisha P Griffin, Dagan K Hammar, Paul F Hollenberg
According to the Centers for Disease Control and Prevention, the incidence of inflammatory bowel diseases (IBD) is about 1 in 250 people in the United States. The disease is characterized by chronic or recurring inflammation of the gut. Because of the localization of the endocannabinoid system in the gastrointestinal tract, it may be a potential pharmacologic target for the treatment of IBD and other diseases. Fatty acid amide hydrolase (FAAH) is a potential candidate because it is upregulated in IBD. FAAH hydrolyzes and, as a consequence, inactivates anandamide (AEA), a prominent endocannabinoid...
June 2016: Journal of Pharmacology and Experimental Therapeutics
Aneesh Karkhanis, Hui Yuan Lam, Gopalakrishnan Venkatesan, Siew Kwan Koh, Christina Li Lin Chai, Lei Zhou, Yanjun Hong, Pipin Kojodjojo, Eric Chun Yong Chan
Dronedarone, a multiple ion channel blocker is prescribed for the treatment of paroxysmal and persistent atrial fibrillation. While dronedarone does not precipitate toxicities like its predecessor amiodarone, its clinical use has been associated with idiosyncratic hepatic and cardiac adverse effects and drug-drug interactions (DDIs). As dronedarone is a potent mechanism-based inactivator of CYP3A4 and CYP3A5, a question arose if it exerts a similar inhibitory effect on CYP2J2, a prominent cardiac CYP450 enzyme...
May 1, 2016: Biochemical Pharmacology
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