药学学报, 2017, 52(1): 26-33
马虹莹, 宁静, 葛广波, 杨凌, 郝大程. 人细胞色素P450酶2J2的功能及其配体研究进展[J]. 药学学报, 2017, 52(1): 26-33.
MA Hong-ying, NING Jing, GE Guang-bo, YANG Ling, HAO Da-cheng. Research progress of human cytochrome P450 2J2 and its ligands[J]. Acta Pharmaceutica Sinica, 2017, 52(1): 26-33.

马虹莹1,2, 宁静2, 葛广波2, 杨凌2, 郝大程1
1. 大连交通大学环境化工学院/生物技术研究所, 辽宁 大连 116028;
2. 中国科学院大连化学物理研究所药用资源开发组, 辽宁 大连 116023
细胞色素酶P450 2J2(cytochrome P450 2J2,CYP2J2)广泛分布于人体多个组织,参与众多内源性化合物和外源性药物的代谢。CYP2J2可催化花生四烯酸(arachidonic acid,AA)生成具有多种生理功能的环氧化二十碳三烯甘油酸(expoxyeicosatrienoic acids,EETs),进而在调节心血管功能和肿瘤发生发展中发挥重要作用。此外,CYP2J2在阿司咪唑、依巴斯汀和特非那定等临床药物的肠道代谢中也发挥关键作用,是多种药物肠道首过代谢环节的重要屏障。本综述结合国内外新近研究进展,系统介绍了CYP2J2的分布、功能及催化特征,CYP2J2功能的表征方法和探针底物研究现状、药物等外源物对CYP2J2的调节作用以及CYP2J2与人类疾病间的关系等,旨在使国内医药领域的研究者更加深入地了解CYP2J2的功能及其在疾病发生发展中的作用。本文通过对近年来CYP2J2配体(底物和抑制剂)研究进展的总结,以期为以CYP2J2为靶点的新药研发提供指导和参考。
关键词:    CYP2J2      代谢      疾病      探针底物      CYP2J2抑制剂     
Research progress of human cytochrome P450 2J2 and its ligands
MA Hong-ying1,2, NING Jing2, GE Guang-bo2, YANG Ling2, HAO Da-cheng1
1. School of Environment and Chemical Engineering, Dalian Jiaotong University, Dalian 116028, China;
2. Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
Cytochrome P4502J2 (CYP2J2) is widely distributed in various human tissues and takes a part in the metabolism of endogenous compounds and drugs. CYP2J2 can convert arachidonic acid (AA) to expoxyeicosatrienoic acids (EETs), which have various biological effects, implying the important role of CYP2J2 in the regulation of cardiovascular system and promotion of tumor progression and metastasis. Additionally, CYP2J2 plays an indispensable role in the intestinal metabolism of various drugs, such as astemizole, terfenadine and ebastine. In this review, the metabolic function, characteristic of catalysis and tissue distribution of CYP2J2 are discussed with the latest literatures both in China and abroad. The state-of-the-art methods for characterization of CYP2J2 and current trend of substrate discovery as well as its relationship with disease are highlighted. This review gives in-depth understanding of the function of CYP2J2 and its role in disease advance. The information of ligand (substrate and inhibitor) will provide the theoretical guidance and reference to the development of novel drugs for CYP2J2.
Key words:    CYP2J2    metabolism    human disease    probe substrate    CYP2J2 inhibitor   
收稿日期: 2016-06-15
DOI: 10.16438/j.0513-4870.2016-0573
基金项目: 国家自然科学基金资助项目(81503152,81573501);辽宁省自然科学基金资助(2015020663);辽宁省研究生教育教学改革研究项目(2016).
通讯作者: 葛广波,Tel:86-411-84379317,Fax:86-411-84676961,E-mail:geguangbo@dicp.ac.cn;hao@djtu.edu.cn
Email: geguangbo@dicp.ac.cn;hao@djtu.edu.cn
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马虹莹  在本刊中的所有文章
宁静  在本刊中的所有文章
葛广波  在本刊中的所有文章
杨凌  在本刊中的所有文章
郝大程  在本刊中的所有文章

[1] Arnold C, Markovic M, Blossey K, et al. Arachidonic acidmetabolizing cytochrome P450 enzymes are targets of ω-3 fatty acids[J]. J Biol Chem, 2010, 285:32720-32733.
[2] Delozier TC, Kissling GE, Coulter SJ, et al. Detection of human CYP2C8, CYP2C9, and CYP2J2 in cardiovascular tissues[J]. Drug Metab Dispos, 2007, 35:682-688.
[3] Dutheil F, Dauchy S, Diry M, et al. Xenobiotic-metabolizing enzymes and transporters in the normal human brain:regional and cellular mapping as a basis for putative roles in cerebral function[J]. Drug Metab Dispos, 2009, 37:1528-1538.
[4] Enayetallah AE, French RA, Thibodeau MS, et al. Distribution of soluble epoxide hydrolase and of cytochrome P4502C8, 2C9, and 2J2 in human tissues[J]. J Histochem Cytochem, 2004, 52:447-454.
[5] Zeldin DC, Foley J, Ma J, et al. CYP2J subfamily P450s in the lung:expression, localization, and potential functional significance[J]. Mol Pharmacol, 1996, 50:1111-1117.
[6] Xie F, Ding XX, Zhang QY. An update on the role of intestinal cytochrome P450 enzymes in drug disposition[J]. Acta Pharm Sin B, 2016, 6:374-383.
[7] Zeldin DC, Foley J, Boyle JE, et al. Predominant expression of an arachidonate epoxygenase in islets of Langerhans cells in human and rat pancreas[J]. Endocrinology, 1997, 138:1338-1346.
[8] Node K, Huo Y, Ruan X, et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids[J]. Science, 1999, 285:1276-1279.
[9] Bertrand-Thiebault C, Ferrari L, Boutherin-Falson O, et al. Cytochromes P450 are differently expressed in normal and varicose human saphenous veins:linkage with varicosis[J]. Clin Exp Pharmacol Physiol, 2004, 31:295-301.
[10] Hsu A, Granneman GR, Witt G, et al. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects[J]. Antimicrob Agents Chemother, 1997, 41:898-905.
[11] Alsaad AM, Zordoky BN, El-Sherbeni AA, et al. Chronic doxorubicin cardiotoxicity modulates cardiac cytochrome P450-mediated arachidonic acid metabolism in rats[J]. Drug Metab Dispos, 2012, 40:2126-2135.
[12] Wu Z, Lee D, Joo J, et al. CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems[J]. Antimicrob Agents Chemother, 2013, 57:5448-5456.
[13] Yamasaki T, Izumi S, Ide H, et al. Identification of a novel rat microsomal vitamin D3 25-hydroxylase[J]. J Biol Chem, 2004, 279:22848-22856.
[14] Zhu J, DeLuca HF. Vitamin D 25-hydroxylase-four decades of searching, are we there yet?[J]. Arch Biochem Biophys, 2012, 523:30-36.
[15] Hashizume T, Imaoka S, Mise M, et al. Involvement of CYP2J2 and CYP4F12 in the metabolism of ebastine in human intestinal microsomes[J]. J Pharmacol Exp Ther, 2002, 300:298-304.
[16] Lee CA, Neul D, Clouser-Roche A, et al. Identification of novel substrates for human cytochrome P4502J2[J]. Drug Metab Dispos, 2010, 38:347-356.
[17] Ghosal A, Lu X, Penner N, et al. Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348(Vorapaxar), a potent oral thrombin proteaseactivated receptor 1 antagonist[J]. Drug Metab Dispos, 2011, 39:30-38.
[18] Liu KH, Kim MG, Lee DJ, et al. Characterization of ebastine, hydroxyebastine, and carebastine metabolism by human liver microsomes and expressed cytochrome P450 enzymes:major roles for CYP2J2 and CYP3A[J]. Drug Metab Dispos, 2006, 34:1793-1797.
[19] Yoo HH, Kim NS, Lee J, et al. Characterization of human cytochrome P450 enzymes involved in the biotransformation of eperisone[J]. Xenobiotica, 2009, 39:1-10
[20] Walker VJ, Griffin AP, Hammar DK, et al. Metabolism of anandamide by human cytochrome P4502J2 in the reconstituted system and human intestinal microsomes[J]. J Pharmacol Exp Ther, 2016, 357:537-544.
[21] Lee B, Wu Z, Liu KH. Response to comment:"a note on CYP2J2-mediated terfenadine hydroxylation in human liver microsomes"[J]. Food Chem Toxicol, 2014, 71:286-287.
[22] Kaspera R, Kirby BJ, Sahele T, et al. Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo[J]. Biochem Pharmacol, 2014, 91:109-118.
[23] Uehara S, Uno Y, Inoue T, et al. Marmoset cytochrome P4502J2 mainly expressed in small intestines and livers effectively metabolizes human P4502J2 probe substrates, astemizole and terfenadine[J]. Xenobiotica, 2016, 46:977-985.
[24] Xia XL, Fa BT, Cong S, et al. Research/review:insights into the mutation-induced dysfunction of arachidonic acid metabolism from modeling of human CYP2J2[J]. Curr Drug Metab, 2014, 15:502-513.
[25] Li W, Tang Y, Liu H, et al. Probing ligand binding modes of human cytochrome P4502J2 by homology modeling, molecular dynamics simulation, and flexible molecular docking[J]. Proteins, 2008, 71:938-949.
[26] Lee CA, Jones JR, Katayama J, et al. Identifying a selective substrate and inhibitor pair for the evaluation of CYP2J2 activity[J]. Drug Metab Dispos, 2012, 40:943-951.
[27] Dai ZR, Ge GB, Feng L, et al. A highly selective ratiometric two-photon fluorescent probe for human cytochrome P4501A[J]. J Am Chem Soc, 2015, 137:14488-14495.
[28] Jin Q, Feng L, Wang DD, et al. A two-photon ratiometric fluorescent probe for imaging carboxylesterase 2 in living cells and tissues[J]. ACS Appl Mater Interfaces, 2015, 7:28474-28481.
[29] Lü X, Ge GB, Feng L, et al. An optimized ratiometric fluorescent probe for sensing human UDP-glucuronosyltransferase 1A1 and its biological applications[J]. Biosens Bioelectron, 2015, 72:261-267.
[30] Lee B, Wu Z, Sung SH, et al. Potential of decursin to inhibit the human cytochrome P4502J2 isoform[J]. Food Chem Toxicol, 2014, 70:94-99.
[31] Lafite P, Dijols S, Zeldin DC, et al. Selective, competitive and mechanism-based inhibitors of human cytochrome P4502J2[J]. Arch Biochem Biophys, 2007, 464:155-168.
[32] Lee E, Wu Z, Shon JC, et al. Danazol inhibits cytochrome P4502J2 activity in a substrate-independent manner[J]. Drug Metab Dispos, 2015, 43:1250-1253.
[33] Yoon YJ, Liu KH. Potential of hydroxyebastine and terfenadine alcohol to inhibit the human cytochrome P4502J2 isoform[J]. J Korean Appl Biochem Chem, 2011, 54:659-666.
[34] Ren S, Zeng J, Mei Y, et al. Discovery and characterization of novel, potent, and selective cytochrome P4502J2 inhibitors[J]. Drug Metab Dispos, 2013, 41:60-71.
[35] El-Serafi I, Fares M, Abedi-Valugerdi M, et al. Cytochrome P4502J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies[J]. Pharmacogenomics J, 2015, 15:405-413.
[36] Wu ZX, Lee B, Kim SY, et al. Inhibitory potential of thelephoric acid and TSAHC on CYP2J2 activites in human liver microsomes[J]. Drug Metab Rev, 2015, 47:65-65
[37] Jeon YJ, Kim JS, Hwang GH, et al. Inhibition of cytochrome P4502J2 by tanshinone IIA induces apoptotic cell death in hepatocellular carcinoma HepG2 cells[J]. Eur J Pharmacol, 2015, 764:480-488.
[38] Karkhanis A, Lam HY, Venkatesan G, et al. Multiple modes of inhibition of human cytochrome P4502J2 by dronedarone, amiodarone and their active metabolites[J]. Biochem Pharmacol, 2016, 107:67-80.
[39] Chen W, Yang S, Ping W, et al. CYP2J2 and EETs protect against lung ischemia/reperfusion injury via anti-inflammatory effects in vivo and in vitro[J]. Cell Physiol Biochem, 2015, 35:2043-2054.
[40] Narjoz C, Favre A, McMullen J, et al. Important role of CYP2J2 in protein kinase inhibitor degradation:a possible role in intratumor drug disposition and resistance[J]. PLoS One, 2014, 9:e95532.
[41] Yan H, Catania C, Bazan GC. Membrane-intercalating conjugated oligoelectrolytes:impact on bioelectrochemical systems[J]. Adv Mater, 2015, 27:2958-2973.
[42] Xu M, Ju W, Hao H, et al. Cytochrome P4502J2:distribution, function, regulation, genetic polymorphisms and clinical significance[J]. Drug Metab Rev, 2013, 45:311-352.
[43] Chen C, Wang DW. Cytochrome P450-CYP2 familyepoxygenase role in inflammation and cancer[J]. Adv Pharmacol, 2015, 74:193-221.
[44] Park SW, Heo DS, Sung MW. The shunting of arachidonic acid metabolism to 5-lipoxygenase and cytochrome P450 epoxygenase antagonizes the anti-cancer effect of cyclooxygenase-2 inhibition in head and neck cancer cells[J]. Cell Oncol (Dordr), 2012, 35:1-8.
[45] Jiang JG, Ning YG, Chen C, et al. Cytochrome P450 epoxygenase promotes human cancer metastasis[J]. Cancer Res, 2007, 67:6665-6674.
[46] Yan H, Kong Y, He B, et al. CYP2J2 rs890293 polymorphism is associated with susceptibility to Alzheimer's disease in the Chinese Han population[J]. Neurosci Lett, 2015, 23:56-60.
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