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Xiao-Yan Huang, Yu-Guang Wang, Yi Wang, Yue Gao
This study aimed to investigate the effect and mechanism of ophiopogonin D (OP-D) on Ang Ⅱ-induced HUVECs apoptosis, in order to provide a reliable basis for the safety and efficacy of traditional Chinese medicines. The effect of Ang Ⅱ on survival and total proteins content of HUVECs were measured by MTT and Western blotting. The effect of OP-D on Ang Ⅱ-induced lactate dehydrogenase (LDH) release rate in HUVECs was measured by enzyme standard instrument. The effects of OP-D and 11,12-EET on phosphorylation of JNK/c-Jun induced by Ang Ⅱ were measured by Western blot and RT-PCR with the help of JNK specific inhibitor SP600125 and CYP450 isozymes selective inhibitor 6-(2-propargyloxyphenyl) hexanoic acid (PPOH)...
January 2018: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Jian Lu, Daozhi Liu, Xiaojing Zhou, Ang Chen, Zhenran Jiang, Xiyun Ye, Mingyao Liu, Xin Wang
BACKGROUND: Cytochrome P450 2J2 (CYP2J2) is not only highly expressed in many kinds of human tumors, but also promotes tumor cell growth via regulating the metabolism of arachidonic acids. CYP2J2 inhibitors can significantly reduce proliferation, migration and promote apoptosis of tumor cells by inhibiting epoxyeicosatrienoic acids (EETs) biosynthesis. Therefore screening CYP2J2 inhibitors is a significant way for the development of anti-cancer drug. PURPOSE: The aim of this study was to identify a new CYP2J2 inhibitor from fifty natural compounds obtained from plants...
January 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Chi Zhou, Jin Huang, Qing Li, Chenao Zhan, Xizhen Xu, Xu Zhang, Ding Ai, Yi Zhu, Zheng Wen, Dao Wen Wang
Chronic excessive drinking leads to myocardial contractile dysfunction and dilated cardiomyopathy, where ethanol toxicity plays an essential role. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the cardiovascular system, but their role in alcoholic cardiomyopathy is elusive. This study was designed to evaluate the effects and mechanisms of CYP2J2 gene delivery on ethanol-induced myocardial dysfunction with focus on autophagy and apoptosis...
February 7, 2018: Free Radical Biology & Medicine
Albert P Li, Ming-Chih David Ho, Kirsten Amaral, Carol Loretz
We report here a novel experimental system - MetMax™ cryopreserved human hepatocytes (MMHH), for in vitro drug metabolism studies. MMHH consist of cofactor-supplemented permeabilized cryopreserved human hepatocytes. The use procedures for MMHH are significantly simplified from that for conventional cryopreserved human hepatocytes (CCHH): 1. Storage at -80o C instead of in liquid nitrogen; 2. Usage directly after thawing without centrifugation and microscopic evaluation of cell density and viability and cell density adjustment...
January 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Eric A Evangelista, Rozenn Lemaitre, Nona Sotoodehnia, Sina Gharib, Rheem A Totah
CYP2J2 is a drug metabolizing enzyme that is highly expressed in adult ventricular myocytes. It is responsible for the bioactivation of arachidonic acid (AA) into epoxyeicosatrienoic acids (EETs). EETs are biologically active signaling compounds that protect against disease progression, particularly in cardiovascular diseases. As a drug-metabolizing enzyme, CYP2J2 is susceptible to drug interactions that could lead to cardiotoxicity. Previously, CYP2J2 has been shown to be resistant to induction by canonical CYP inducers such as phenytoin and rifampin...
January 17, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Yan Yang, Ruolan Dong, Zhihui Chen, Danli Hu, Menglu Fu, Ying Tang, Dao Wen Wang, Xizhen Xu, Ling Tu
Ample evidences demonstrate that cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti-inflammatory, and cardiovascular protective effects. In this study, we investigated the effects of endothelium-specific CYP2J2 overexpression on age-related insulin resistance and metabolic dysfunction. Endothelium-specific targeting of the human CYP epoxygenase, CYP2J2, transgenic mice (Tie2-CYP2J2-Tr mice) was utilized. The effects of endothelium-specific CYP2J2 overexpression on aging-associated obesity, inflammation, and peripheral insulin resistance were evaluated by assessing metabolic parameters in young (3 months old) and aged (16 months old) adult male Tie2-CYP2J2-Tr mice...
January 10, 2018: Aging Cell
Guangzhao Qi, Duolu Li, Xiaojian Zhang
Interindividual and interethnic variability of drug responses could be attributed to the differences of genetic polymorphisms in the drug metabolizing enzymes and transporters genes among the populations. Here we reviewed the studies of genetic variations in Uyghur Chinese of fifteen CYP450 genes including CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2W1, CYP3A4, CYP3A5, CYP4A11, and CYP17A1, which totally covered 277 variants. We also collected the data of 277 variants covered in our study in two extensive population sequencing projects, the International HapMap Project (Hap-Map) and the 1000 Genomes Project and compared them with the data of Uyghur Chinese...
February 2018: Drug Metabolism and Pharmacokinetics
William R Arnold, Javier L Baylon, Emad Tajkhorshid, Aditi Das
Doxorubicin (DOX) is a chemotherapeutic that is used in the treatment of a wide variety of cancers. However, it causes cardiotoxicity partly because of the formation of reactive oxygen species. CYP2J2 is a human cytochrome P450 that is strongly expressed in cardiomyocytes. It converts arachidonic acid (AA) into four different regioisomers of epoxyeicosatrienoic acids (EETs). Using kinetic analyses, we show that AA metabolism by CYP2J2 is modulated by DOX. We show that cytochrome P450 reductase, the redox partner of CYP2J2, metabolizes DOX to 7-deoxydoxorubicin aglycone (7-de-aDOX)...
December 26, 2017: Biochemistry
Geun Hye Hwang, So Mi Park, Ho Jae Han, Kyoung Min Baek, Joong Sun Kim, Woochul Chang, Ho Jin Lee, Seung Pil Yun, Jung Min Ryu, Min Young Lee
The present study examined the role of human cytochrome P450 2J2 (CYP2J2) on cell proliferation and resistance to an anticancer agent using stable hepatocellular carcinoma HepG2 cells overexpressing CYP2J2. Overexpression of CYP2J2 significantly increased HepG2 cell proliferation and the expression levels of cell cycle regulatory proteins, including cyclin D1, cyclin E, cyclin-dependent kinase (Cdk)2 and Cdk4. CYP2J2-overexpressing HepG2 cells exhibited high levels of Akt phosphorylation compared with those observed in wild-type HepG2 cells...
November 2017: Oncology Letters
Ming Yao, Daping Lv, Jiajia Huo, Zhongwu Sun
BACKGROUND: Cerebral small vessel disease (SVD) can cause cognitive impairment, disability, and dementia. While it's still unclear about the pathogenesis of SVD, several risk factors of SVD have been identified, and studies suggested that hypertension may play a critical role in SVD. Furthermore, studies have demonstrated that CYP2J2 isoform, 50 G>T variant, is associated with increase the risk of ischemic stroke. Thus, we hypothesized that CYP2J2 50 G>T variant is associated with increased risk of cerebral SVD...
October 17, 2017: Current Neurovascular Research
Haruna Nagayoshi, Kensaku Kakimoto, Yoshimasa Konishi, Keiji Kajimura, Takeshi Nakano
2,2',3,5',6-Pentachlorobiphenyl (PCB 95) and 2,2',3,4,4',5',6-heptachlorobiphenyl (PCB 183) possess axial chirality and form the aS and aR enantiomers. The enantiomers of these congeners have been reported to accumulate in the human body enantioselectively via unknown mechanisms. In this study, we determined the cytochrome P450 (CYP) monooxygenase responsible for the enantioselective oxidization of PCB 95 and PCB 183, using a recombinant human CYP monooxygenase. We evaluated 13 CYP monooxygenases, namely CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, CYP3A4, CYP3A5, CYP4F2, and aromatase (CYP19), and revealed that CYP2A6 preferably oxidizes aS-PCB 95 enantioselectively; however, it did not oxidize PCB 183...
October 17, 2017: Environmental Science and Pollution Research International
Guillermo Gervasini, Enrique Luna, Guadalupe Garcia-Pino, Lilia Azevedo, Sonia Mota-Zamorano, Juan José Cubero
OBJECTIVE: Arachidonic acid metabolism by cytochrome P450 (CYP) epoxygenases leads to epoxyeicosatrienoic acids (EETs), which are eicosanoids with vasodilator and anti-inflammatory properties. We aim to determine whether genetic variability in these routes may contribute to cardiovascular (CV) risk in renal transplant recipients. METHODS: In a cohort of 355 patients, we determined the presence of two polymorphisms, CYP2C8*3 and CYP2J2*7, known to affect eicosanoid levels...
November 8, 2017: Current Medical Research and Opinion
Aneesh Karkhanis, Nhan Dai Thien Tram, Eric Chun Yong Chan
Cardiac enzymes such as cytochrome P450 2J2 (CYP2J2) metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs), which in turn are metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). As EETs and less potent DHETs exhibit cardioprotective and vasoprotective functions, optimum levels of cardiac EETs are paramount in cardiac homeostasis. Previously, we demonstrated that dronedarone, amiodarone and their main metabolites, namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA), potently inhibit human cardiac CYP2J2-mediated astemizole metabolism in vitro...
December 15, 2017: Biochemical Pharmacology
Markus Drag, Ruta Skinkyté-Juskiené, Duy N Do, Lisette J A Kogelman, Haja N Kadarmideen
Boar taint (BT) is an offensive odour or taste observed in pork from a proportion of non-castrated male pigs. Surgical castration is effective in avoiding BT, but animal welfare issues have created an incentive for alternatives such as genomic selection. In order to find candidate biomarkers, gene expression profiles were analysed from tissues of non-castrated pigs grouped by their genetic merit of BT. Differential expression analysis revealed substantial changes with log-transformed fold changes of liver and testis from -3...
September 22, 2017: Scientific Reports
Jian Chen, Dong-Fei Wang, Guo-Dong Fu, Jie Ding, Lei-Yang Chen, Jia-Lan Lv, Juan Fang, Xiang Yin, Xiao-Gang Guo
The association of the CYP2J2 G-50T polymorphism with coronary artery disease has been explored, but the results remain controversial. Thus, a meta-analysis was conducted to provide a comprehensive estimate of this association. We selected ten articles encompassing 12 independent case-control studies with 7063 cases and 10,453 controls for this meta-analysis. Overall, we found significant associations between the CYP2J2 G-50T polymorphism and coronary artery disease risk in three genetic models (allele model: odds ratio (OR) = 1...
August 29, 2017: Oncotarget
Jae-Kyung Heo, Phi-Hung Nguyen, Won Cheol Kim, Nguyen Minh Phuc, Kwang-Hyeon Liu
Selaginella tamariscina (Beauv.) has been used for traditional herbal medicine for treatment of cancer, hepatitis, and diabetes in the Orient. Numerous bioactive compounds including alkaloids, flavonoids, lignans, and selaginellins have been identified in this medicinal plant. Among them, selaginellins having a quinone methide unit and an alkylphenol moiety have been known to possess anticancer, antidiabetic, and neuroprotective activity. Although there have been studies on the biological activities of selaginellins, their modulatory potential of cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyltransferase (UGT) activities have not been previously evaluated...
September 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Ruolan Dong, Danli Hu, Yan Yang, Zhihui Chen, Menglu Fu, Dao Wen Wang, Xizhen Xu, Ling Tu
Integrity of endothelial barrier is a determinant of the prognosis in the acute lung injury caused by sepsis. The epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, exhibit protective effects in various pathogenic states, however, whether EETs play a role in endothelial barrier enhancement and the involved mechanisms remain to be investigated. Here, we show that increased EETs level by endothelial specific cytochrome P450 epoxygenase 2J2 over-expression and soluble epoxide hydrolase (sEH) inhibitor TPPU reduced lipopolysaccharide-induced endothelial hyper-permeability in vivo, accompanied by improved survival of septic mice...
August 1, 2017: Oncotarget
Yuka Kato, Yuji Mukai, Anders Rane, Nobuo Inotsume, Takaki Toda
Epoxyeicosatorienoic acids (EETs) are generated from arachidonic acid (AA) by CYPs. EETs comprise four regioisomers (14,15-, 11,12-, 8,9-, and 5,6-EET). EETs show potent physiological effects, including vasodilation, anti-inflammation, myocardial preconditioning, and anti-platelet aggregation effects. We recently demonstrated that telmisartan, one of angiotensin II receptor blockers, inhibits AA metabolism by CYP enzymes, including CYP2C8, CYP2C9, and CYP2J2. We conducted studies of AA metabolism using recombinant CYP enzymes to estimate the inhibition constant and the type of inhibition by telmisartan of CYP2C9 and CYP2C8...
2017: Biological & Pharmaceutical Bulletin
Jong Cheol Shon, Nguyen Minh Phuc, Won Cheol Kim, Jae Kyung Heo, Zhexue Wu, Hyunyoung Lee, Kwang-Hyeon Liu
Acetylshikonin is a biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the roots of Lithospermum erythrorhizoma. An inhibitory effect of acetylshikonin against CYP2J2 activity was discovered recently. Based on this result, this study was expanded to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed a strong inhibitory effect against all P450s tested with IC50 values of 1...
December 2017: Biopharmaceutics & Drug Disposition
Barry C Jones, Roshini Markandu, Chungang Gu, Graeme Scarfe
In hepatic S9 and human liver microsomes (HLM) the sulfoximine moiety of the ATR inhibitor AZD6738 is metabolised to its corresponding sulfoxide (AZ8982) and sulfone (AZ0002). The initial de-imination to AZ8982 is nominally a reductive reaction but in HLM required NADPH and was inhibited by 1-aminobenzotriazole (ABT) at 1mM. Studies in a panel of 11 recombinant cytochrome P450s (CYPs) - CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 CYP2J2, CYP3A4 and CYP3A5 - confirmed that the de-imination was an oxidative process, mediated largely by CYP2C8 with some CYP2J2 involvement, whilst the subsequent oxidation to the sulfone was carried out largely by CYP2J2, CYP3A4 and CYP3A5...
August 23, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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