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Article(id=1218263312219951445, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263310198296916, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2016-0573, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1465920000000, receivedDateStr=2016-06-15, revisedDate=1468857600000, revisedDateStr=2016-07-19, acceptedDate=null, acceptedDateStr=null, onlineDate=1768386207871, onlineDateStr=2026-01-14, pubDate=1484150400000, pubDateStr=2017-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768386207871, onlineIssueDateStr=2026-01-14, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768386207871, creator=13701087609, updateTime=1768386207871, updator=13701087609, issue=Issue{id=1218263310198296916, tenantId=1146029695717560320, journalId=1189982191388893191, year='2017', volume='52', issue='1', pageStart='1', pageEnd='179', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768386207389, creator=13701087609, updateTime=1768386435964, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218264268965856067, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263310198296916, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218264268965856068, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263310198296916, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=26, endPage=33, ext={EN=ArticleExt(id=1218263312777793885, articleId=1218263312219951445, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research progress of human cytochrome P450 2J2 and its ligands, columnId=1218263312677130587, journalTitle=Acta Pharmaceutica Sinica, columnName=SPECIAL REPORTS, runingTitle=null, highlight=null, articleAbstract=

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.

, correspAuthors=Guang-bo GE, Da-cheng HAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright © 2016 ACTA PHARMACEUTICA SINICA All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Hong-ying MA, Jing NING, Guang-bo GE, Ling YANG, Da-cheng HAO), CN=ArticleExt(id=1218263313557934437, articleId=1218263312219951445, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=人细胞色素P450酶2J2的功能及其配体研究进展, columnId=1218263312865874270, journalTitle=药学学报, columnName=专题报道, runingTitle=null, highlight=null, articleAbstract=

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。

, correspAuthors=葛广波, 郝大程, authorNote=null, correspAuthorsNote=
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Adv Pharmacol, 2015, 74:193-221., articleTitle=null, refAbstract=null), Reference(id=1218968399292580158, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263312219951445, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[44], rfOrder=43, authorNames=null, journalName=null, refType=null, unstructuredReference=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., articleTitle=null, refAbstract=null), Reference(id=1218968399439380812, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263312219951445, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[45], rfOrder=44, authorNames=null, journalName=null, refType=null, unstructuredReference=Jiang JG, Ning YG, Chen C, et al. Cytochrome P450 epoxygenase promotes human cancer metastasis[J]. Cancer Res, 2007, 67:6665-6674., articleTitle=null, refAbstract=null), Reference(id=1218968399586181469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263312219951445, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[46], rfOrder=45, authorNames=null, journalName=null, refType=null, unstructuredReference=Yan H, Kong Y, He B, et al. 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Substrate Metabolic reaction Km /μmol·L-1 Vmax /nmol·min-1·nmol-1 CLint /mL·min-1·nmol-1 Other involved CYPs Reference
Fenbendazole Hydroxylation 0.32 0.62 [12]
Albendazole O-Hydroxylation 1.91 0.65 0.36 [12, 16]
Sulfoxidation 4.23 1.89 3A4
Apixaban O-demethylation 0.27 1A2/3A4 [16]
Astemizole O-demethylation 0.65 1.129 1.14 2D6/4F12 [16]
Benzphetamine N-Demethylation 0.08 [16]
Bufuralol 0.17 [16]
Cyclosporine A Hydroxylation 0.12 3A4 [16]
Danazol 0.29 3A4 [16]
Mesoridazine Sulfoxidation 0.06 3A4 [16]
Nabumetone 0.11 3A4 [16]
Tamoxifen N-Demethylation 0.19 3A4 [16]
Thioridazine Sulfoxidation 0.27 3A4 [16]
Vorapaxar Hydroxylation 0.0306 3A4 [17]
Ebastin Hydroxylation 1.3-18.3 8.2-40.6 0.45-31 4F12 [15, 18]
Hydroxyebastine Carboxylation 0.75 9.86 3A4 [18]
Eperisone ω-Hydroxylation 0.026 6 3A4/4F12 [19]
ω-1 Hydroxylation 2D6/3A4/4F12/1A2/2C9
Anandamide 20-Hydroxyeicosatetraenoic acid Ethanolamide 3A4/2A6/2C9/2D6/2E1/ 1A2/4A11 [20]
Terfenadine Hydroxylation 0.4-1.5 20-29.4 3.98 3A4/2D6/4F12 [16, 21]
Ritonavir Hydroxylation 0.016 2.0 3A4/5/2D6 [10, 22]
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Exogenous substrates of CYP2J2

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Substrate Metabolic reaction Km /μmol·L-1 Vmax /nmol·min-1·nmol-1 CLint /mL·min-1·nmol-1 Other involved CYPs Reference
Fenbendazole Hydroxylation 0.32 0.62 [12]
Albendazole O-Hydroxylation 1.91 0.65 0.36 [12, 16]
Sulfoxidation 4.23 1.89 3A4
Apixaban O-demethylation 0.27 1A2/3A4 [16]
Astemizole O-demethylation 0.65 1.129 1.14 2D6/4F12 [16]
Benzphetamine N-Demethylation 0.08 [16]
Bufuralol 0.17 [16]
Cyclosporine A Hydroxylation 0.12 3A4 [16]
Danazol 0.29 3A4 [16]
Mesoridazine Sulfoxidation 0.06 3A4 [16]
Nabumetone 0.11 3A4 [16]
Tamoxifen N-Demethylation 0.19 3A4 [16]
Thioridazine Sulfoxidation 0.27 3A4 [16]
Vorapaxar Hydroxylation 0.0306 3A4 [17]
Ebastin Hydroxylation 1.3-18.3 8.2-40.6 0.45-31 4F12 [15, 18]
Hydroxyebastine Carboxylation 0.75 9.86 3A4 [18]
Eperisone ω-Hydroxylation 0.026 6 3A4/4F12 [19]
ω-1 Hydroxylation 2D6/3A4/4F12/1A2/2C9
Anandamide 20-Hydroxyeicosatetraenoic acid Ethanolamide 3A4/2A6/2C9/2D6/2E1/ 1A2/4A11 [20]
Terfenadine Hydroxylation 0.4-1.5 20-29.4 3.98 3A4/2D6/4F12 [16, 21]
Ritonavir Hydroxylation 0.016 2.0 3A4/5/2D6 [10, 22]
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Substrate recognition site (SRS) Peptide region Residue
SRS-1 β' Helix Phe56, Leu83, Met116 and Arg117
SRS-2 C-Terminus of F helix Glu222, Gln228, Leu229 and Asn231
SRS-4 Central I helix Phe310
SRS-5 β1-4 Ile376 and Val380
SRS-6 β1 Hairpin Gly486, Ile487 and Thr488
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Key amino acid residues responsible for ligand binding

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Substrate recognition site (SRS) Peptide region Residue
SRS-1 β' Helix Phe56, Leu83, Met116 and Arg117
SRS-2 C-Terminus of F helix Glu222, Gln228, Leu229 and Asn231
SRS-4 Central I helix Phe310
SRS-5 β1-4 Ile376 and Val380
SRS-6 β1 Hairpin Gly486, Ile487 and Thr488
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Inhibitor Substrate IC50 /μmol·L-1 Ki /μmol·L-1 Type of inhibition Inhibition of other CYPs (IC50 < 10 μmol·L-1) Reference
Decursin Astemizole 10.18 8.34 Uncompetitive inhibition [30]
Terfenadine 1.8 15.8 Uncompetitive inhibition
4-Hydroxytoremifene Astemizole 8.4 11.1 Uncompetitive inhibition [32]
Danazol Terfenadine 0.07-0.34 Competitive inhibition CYP2C8, 2D6, 2C9 [32]
Astemizole 0.07 0.02-0.06 Uncompetitive inhibition
Albendazole 0.05
Ebsatine 0.18
Terfenadone Albendazole/Astemizole/ Terfenadine/Ebsatine <0.21 CYP3A4, 2B6 [32]
Hydroxyebastine Astemizole 10.9 8.34 [33]
Terfenadine 2.03 15.8
Flunarizine Astemizole 0.94 0.13 Competitive inhibition CYP2D6 [34]
Telmisartan Astemizole 0.42-0.85 0.19 Mixed inhibition CYP2C9 [34, 35]
Thelephoric acid Astemizole 3.23 [36]
Ebsatine 5.32
Terfenadine 3.27
Tanshinone Astemizole 2.5 Uncompetitive inhibition [37]
N-Desbutyldronedarone Astemizole 0.55 Mixed inhibition CYP3A4, 3A5 [38]
N-Desethylamiodarone Astemizole 7.4 Uncompetitive inhibition [38]
Dronedarone Astemizole 0.034 Mixed inhibition CYP3A4, 2D6 [38]
Amiodarone Astemizole 4.8 Uncompetitive inhibition CYP3A4, 3A5 [38]
), ArticleFig(id=1218968390224495263, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263312219951445, language=CN, label=Table 3, caption=

Inhibitors (IC50 < 25 μmol) of human CYP2J2

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Inhibitor Substrate IC50 /μmol·L-1 Ki /μmol·L-1 Type of inhibition Inhibition of other CYPs (IC50 < 10 μmol·L-1) Reference
Decursin Astemizole 10.18 8.34 Uncompetitive inhibition [30]
Terfenadine 1.8 15.8 Uncompetitive inhibition
4-Hydroxytoremifene Astemizole 8.4 11.1 Uncompetitive inhibition [32]
Danazol Terfenadine 0.07-0.34 Competitive inhibition CYP2C8, 2D6, 2C9 [32]
Astemizole 0.07 0.02-0.06 Uncompetitive inhibition
Albendazole 0.05
Ebsatine 0.18
Terfenadone Albendazole/Astemizole/ Terfenadine/Ebsatine <0.21 CYP3A4, 2B6 [32]
Hydroxyebastine Astemizole 10.9 8.34 [33]
Terfenadine 2.03 15.8
Flunarizine Astemizole 0.94 0.13 Competitive inhibition CYP2D6 [34]
Telmisartan Astemizole 0.42-0.85 0.19 Mixed inhibition CYP2C9 [34, 35]
Thelephoric acid Astemizole 3.23 [36]
Ebsatine 5.32
Terfenadine 3.27
Tanshinone Astemizole 2.5 Uncompetitive inhibition [37]
N-Desbutyldronedarone Astemizole 0.55 Mixed inhibition CYP3A4, 3A5 [38]
N-Desethylamiodarone Astemizole 7.4 Uncompetitive inhibition [38]
Dronedarone Astemizole 0.034 Mixed inhibition CYP3A4, 2D6 [38]
Amiodarone Astemizole 4.8 Uncompetitive inhibition CYP3A4, 3A5 [38]
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人细胞色素P450酶2J2的功能及其配体研究进展
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马虹莹 1, 2 , 宁静 2 , 葛广波 2, * , 杨凌 2 , 郝大程 1, *
药学学报 | 专题报道 2017,52(1): 26-33
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药学学报 | 专题报道 2017, 52(1): 26-33
人细胞色素P450酶2J2的功能及其配体研究进展
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马虹莹1, 2, 宁静2, 葛广波2, * , 杨凌2, 郝大程1, *
作者信息
  • 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

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* Tel:86-411-84379317,Fax:86-411-84676961,E-mail:;
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Research progress of human cytochrome P450 2J2 and its ligands
Hong-ying MA1, 2, Jing NING2, Guang-bo GE2, * , Ling YANG2, Da-cheng HAO1, *
Affiliations
  • 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
出版时间: 2017-01-12 doi: 10.16438/j.0513-4870.2016-0573
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摘要
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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。

CYP2J2  /  代谢  /  疾病  /  探针底物  /  CYP2J2抑制剂

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.

CYP2J2  /  metabolism  /  human disease  /  probe substrate  /  CYP2J2 inhibitor
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. 药学学报, 2017 , 52 (1) : 26 -33 . DOI: 10.16438/j.0513-4870.2016-0573
Hong-ying MA, Jing NING, Guang-bo GE, Ling YANG, Da-cheng HAO. Research progress of human cytochrome P450 2J2 and its ligands[J]. Acta Pharmaceutica Sinica, 2017 , 52 (1) : 26 -33 . DOI: 10.16438/j.0513-4870.2016-0573
正文
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细胞色素P450 (cytochrome P450, CYP) 为一类亚铁血红素-硫醇盐蛋白的超家族, 是表达于内质网膜上的混合功能氧化酶系统末端氧化酶, 在多种内源化合物如脂肪酸、维生素、胆固醇及甾体类的代谢激活以及外源物包括药物、致癌物、环境污染物等物质的体内代谢过程中均发挥重要作用。CYP2J2主要表达于肝外组织, 在心肌细胞和主动脉周围的上皮细胞中表达量最高。人CYP2J2首次发现于1996年, 是目前人体中发现的CYP2J亚家族中的唯一成员。CYP2J2作为重要的心血管系统平衡状态调节酶, 通过代谢内源化合物花生四烯酸 (arachidonic acid, AA) 生成具有多种生理功能的表氧化二十碳三烯酸 (expoxyeicosatrienoic acids, EETs) 异构体影响心血管系统的生理及病理状态[1, 2]。CYP2J2 mRNA水平和蛋白表达水平在人肿瘤组织均会上调, 参与癌细胞的增殖和转移。可代谢多种外源化合物, 并在某些药物 (如特非那定、依巴斯汀) 的代谢中发挥重要作用[3]。本文就侧重于目前对人源CYP2J2分布、功能及催化特征、外源药物对CYP2J2的调节作用和CYP2J2配体 (底物和抑制剂) 的研究现状及CYP2J2与人类疾病间的关系、等关键信息进行综述。
1 CYP2J2在人体内的分布
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CYP2J2在人体中分布极为广泛, 除主要分布于心血管系统[2], 在肾[4]、肺[5]、大脑、胃肠道[6]、胰腺[7]、胰岛的 α、β、δ细胞、大脑皮层、海马区及胎儿的鼻腔黏膜等众多组织均有CYP2J2的发现。其中, 对于CYP2J2在心血管组织、肝脏、肠道、肾和脑中的分布研究较为深入。从CYP2J2蛋白表达水平的量来讲, CYP2J2主要表达于心血管组织, 通过催化内源化合物AA生成EETs参与心血管系统的调节; 其次表达于肝脏、肠道和肾脏, 代谢外源化合物和调节体液平衡; 人脑中CYP2J2蛋白的表达量虽然低, 但与阿尔茨海默症息息相关。以下介绍CYP2J2在这几种组织中的分布情况。
1.1 心血管
CYP2J2在人体内主要分布于心血管组织, 以心肌细胞为首, 其次是冠状动脉内皮细胞, 少量分布于冠状动脉平滑肌细胞[8]、主动脉[8]和静脉[9]。在心血管组织, CYP2J2代谢AA生成EETs, 通过EETs的多种生理功能调节心血管系统。
1.2 肝脏、肠道
CYP2J2虽然参与多种外源化合物的代谢, 但CYP2J2在肝、空肠、回肠和结肠中仅占CYP总量的1%～2%[10]。受其含量的限制, 理论上, CYP2J2一般不会对外源物的代谢起决定性作用。然而, 研究发现CYP2J2却在某些药物 (如抗组胺药物特非那定和依巴斯汀) 的肠道代谢中发挥着主导作用[3]。所以, CYP2J2对外源化合物的代谢作用仍不可忽视。
1.3 肾
在肾脏, CYP2J2主要分布于近曲小管 (特别是直部) 和集合管等能量依赖主动转运吸收和分泌的部位。在近曲小管, CYP2J2催化EETs生成, 后者通过抑制Na+的转运, 调节细胞质中的Ca2+对血管紧张素Ⅱ的诱导作用以及抑制Na+\K+腺苷三磷酸酶[11]。在集合管, CYP2J2催化生成的EETs对水、Na+重吸收和K+分泌产生抑制作用, 并刺激前列腺素合成。所以CYP2J2对肾脏生理功能, 特别是调节体液平衡方面起重要作用。
1.4 脑
除了在心脏、肾脏和肝脏等组织中表达, CYP2J2在大脑皮层、额叶和海马区也有很高的表达量。Dutheil等[3]研究表明, 人脑中分布着多种CYP, 而CYP2J2的表达量大约为CYP450总含量的20%。
2 CYP2J2的功能及催化特征
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人CYP2J2对内源物和外源物代谢均具有重要的催化作用。催化代谢花生四烯酸和维生素D3, 对心血管系统的生理病理状态及骨骼钙吸收等进行调节。催化多种外源化合物代谢, 底物结构丰富多样, 倾向于催化化合物末端反应活性位点[12]。
2.1 内源性化合物
2.1.1 花生四烯酸
AA是一种不饱和脂肪酸, 参与众多细胞的信号转导与信号通路的调节。CYP1A、2B、2C、2D、2G、2J、2N和4A等亚家族均参与了由AA生成EETs的代谢过程, 其中CYP2J2因在人心血管系统高表达, 被视为心血管系统中代谢AA的重要酶。在CYP2J2的作用下, AA被代谢为4种具有生物活性的EETs, 包括5, 6-, 8, 9-, 11, 12-和14, 15-EETs。EETs作为一种内源性超极化因子, 具有促进内皮细胞增殖、迁移、类微血管结构形成、抑制血管平滑肌细胞迁移和抗炎等多种生物活性。
2.1.2 维生素D3
维生素D3是体内脂溶性类固醇衍生物, 负责钙、磷酸盐体内平衡和维护骨骼健康。可经皮肤光照而由7-脱氢胆固醇转化而来, 亦可由日常饮食获取。维生素D3的代谢激活过程主要体现为: 在肝脏中的25-羟化酶和肾脏中的1α-羟化酶的相继催化下产生具有重要生物活性的1α, 25-双羟基维生素D3[13]。其中CYP2R1和CYP2J2是人体维生素D3进行25-羟化反应的两种主要代谢酶。CYP2R1的25-羟化反应催化活性高于CYP2J2。CYP2J2对维生素D3的1α-羟化反应的催化效率高于CYP2R1[14]。由于CYP2J2大量分布于肾、肠等肝外组织, 所以认为CYP2J2对肝外局部组织中维生素D3的代谢激活起重要作用。
2.1.3 其他内源性化合物
CYP2J2催化亚油酸生成环氧化十八烯酸 (epoxidation of oleic acid EOA), 以9, 10-和12, 13-EOA为主。而EOA具有诱导线粒体功能障碍的生物毒性[14]。在严重烧伤患者的血浆中9, 10-和12, 13-EOA的浓度会超过100 μmol·L-1 (远高于正常值) , 大大增加了患者的死亡率。
2.2 外源性化合物
自1996年人CYP2J2发现以来, 对其研究主要集中于内源化合物的代谢和心血管系统的调节。直到2002年Hashizume等[15]首次发现CYP2J2可代谢抗组胺药物依巴斯汀。为了明确CYP2J2的底物谱, Lee等[16]研究CYP2J2对139种临床常用药物的催化行为, 发现阿苯达唑、硫醚嗪、达那唑、他莫西芬、环孢霉素A、纳布美通和美索达嗪等具有不同结构母核及结构特征的药物均可被其代谢。由于CYP2J2参与多种药物代谢, 见表 1[10, 12, 15-22], 美国食品药品管理局 (FDA) 2012年的相关文件呼吁医药业研究者关注CYP2J2在药物代谢中的作用[21]。之后的研究发现, CYP2J2的底物选择特异性不高, 会同时被其他CYP酶 (如CYP3A4) 代谢[18-20]。其中胺碘酮和阿苯达唑的4位羟基化反应是现仅有CYP2J2特有的催化代谢过程。虽然, CYP2J2在肝脏和肠道CYP酶分布量中不占优势, 底物选择性不好, 但2014年, Kaspera等[22]证实, 依巴斯汀在肠道中通过CYP2J2途径的代谢率高达70%。Uehara等[23]发现, CYP2J2在人体和兔小肠中阿司咪唑的代谢中起到决定性作用。
2.3 CYP2J2催化特征
CYP2J2可参与化合物的脱烷基、羟化和氧化等多种反应类型。其外源底物和催化反应特征为: ① 底物结构变异大: 从相对刚性结构 (胺碘酮) 到复杂结构 (环孢霉素), 大小结构丰富多样; ② 特殊的区域选择性: CYP2J2倾向于催化化合物末端反应活性较弱的位点。
虽然, 人CYP2J2的晶体结构尚未被鉴定, 但已有研究通过对比CYP2J2与其他CYP亚型的异同来揭示CYP2J2的底物识别、结合、催化机制与特征。CYP3A4是目前发现的与CYP2J2底物谱重叠度最高的CYP。二者比较而言, CYP3A4在催化相同底物时, 反应主要发生在底物化学活性最强的位点上, 更符合CYP的已知催化规律。针对这一现象, Lee等[16]通过CYP2B4、CYP2C8和CYP2A6的晶体结构同源模型构建CYP2J2空间结构, 发现CYP2J2与CYP3A4虽然具有相似的活性空腔体积 (1 420 Å与 1 585 Å), 但二者活性空腔的结构存在显著差异。已知CYP家族亚铁血红素活性基团被限制在螺旋I和邻近的螺旋β-4之间, CYP2J2活性空腔的宽度 (从丙氨酸277到缬氨酸346) 为9.4 Å, 而CYP3A4活性空腔的宽度 (从丙氨酸305到谷氨酸374) 为15.1 Å。所以尽管CYP2J2的活性空腔体积和3A4的一样大, 可以容纳大的底物, 但在拓扑结构上它的活性空腔比3A4窄, 因此倾向于容纳底物中更易接近血红素铁活性位点的部分。Lee等[16]针对CYP3A4和CYP2J2对于阿苯达唑、胺碘酮、阿司咪唑、硫醚嗪、美索达嗪和达那唑等的催化选择性, 从实验角度证实CYP2J2更倾向于代谢底物容易进入狭窄空腔的末端活性位点。
此外, 某些氨基酸会对CYP2J2的催化功能造成影响。一些基因多态性, 如具有T143A、R158C、I192N 或 N404Y突变的CYP2J2会显著降低对AA的代谢, 使冠状动脉疾病恶化。为了揭示小分子配体 (如AA) 与CYP2J2相互作用的机制, Xia等[24]基于CYP2A6、CYP2E1、CYP2C8、CYP2R1和CYP17A1的晶体结构, 构建了CYP2J2的3D结构模型。通过研究AA与CYP2J2的相互作用模式, 发现Gly486和Leu378受体活性位点通过氢键相互作用在识别和定位配体 (AA) 羧基中起关键作用。已知的T143A、R158C、I192N、N404Y和G50T突变中的任何一种都会直接或间接地影响其他几种突变, 进而引起CYP2J2代谢AA的功能异常。此外, Li等[25]基于CYP2C9的晶体结构同源模建了CYP2J2的3D结构。根据CYP2家族结构特征, 推测CYP2J2有6个底物结合区域, 且底物结合区域的某些关键氨基酸, 对底物的识别及结合有重要作用 (表 2) 。
3 CYP2J2的探针底物研究进展
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一方面, CYP2J2广泛分布于人体, 代谢内源化合物调节心血管系统和体液平衡, 其活性密切联系于多种疾病的发生发展。另一方面, 虽然尚未完全明确CYP2J2在药物代谢中所扮演的角色, 但它广泛的底物谱和对依巴斯汀等药物的主导代谢作用均表明其可能在药物代谢和药物之间相互作用中起重要作用。既然CYP2J2的功能与多种疾病、药物代谢都表现出一定的关联性, 因此对CYP2J2的活性评价工作就不容小觑。而为了描述CYP2J2在疾病发生发展及药物代谢中的作用, 建立高效表征CYP2J2功能水平的评价方法具有重要意义。
目前, 应用最为广泛的评价蛋白功能水平的方法就是借助目标蛋白的特异性底物, 通过监测产物的生成或底物的消减实现蛋白的活性评价。在这一过程中, 特异性底物就是目标蛋白功能水平的探针。虽然相关研究已逐步揭示CYP2J2底物繁多、结构各异。但CYP2J2的探针底物研究刚刚起步, 仍缺少以此为课题的系统研究与报道。目前, 依巴斯汀、胺碘酮、阿司咪唑和阿苯达唑是较常用的在体外实验中用于表征CYP2J2活性的探针底物。而三者均是临床药物, 在催化特异性和检测通量等方面存在或多或小的缺陷。就参与的CYP450催化选择性而言: 除CYP2J2外, 依巴斯汀还会被4F12代谢, 胺碘铜和阿苯达唑会被3A4代谢, 而阿司咪唑会被2D6、4F12代谢。就代谢区域选择性而言, Lee等[26]研究发现胺碘酮经CYP代谢会生成N-去乙基和4位羟化两种代谢产物, 4位羟基化是一个没有CYP3A4参与的CYP2J2代谢过程。阿苯达唑虽可以被3A4氧化, 但4位羟化反应3A4几乎不参与, 体内清除率比值为0.36, 是目前选择性最好的评价CYP2J2活性的探针反应。需要注意的是, 以上两种探针底物的特定代谢产物的检测与定量需要依赖于质谱、液相等大型仪器检测分析, 存在耗时长、操作繁琐、不能进行高通量检测等问题。
近年来小分子荧光探针底物由于其特异性好、灵敏度高、操作简单、适于高通量筛选等优势, 得到了国内外学者的广泛关注。研发选择性专一、灵敏度高、抗环境干扰能力强的代谢酶荧光探针底物, 不仅可用于复杂生物样本中目标酶的活性检测、个体及种属差异研究、酶抑制剂或诱导剂的高通量筛选, 还可为深入研究代谢酶功能与人体疾病发生发展间的关系等研究提供强有力的工具分子。目前, 基于目标酶的催化特性及其偏好底物的结构特征来设计研发代谢酶特异性荧光探针底物已成为该领域的共识。例如, Dai等[27]依据CYP1A酶催化活性中心多丝氨酸这一特性, 以及该酶偏好催化多环芳烃类化合物的O-去烷基反应这一特征, 以1, 8-萘酰亚胺为母体, 通过对系列1, 8-萘酰亚胺衍生物的筛选和反复优化, 成功研制出了CYP1A的特异性双光子荧光探针NCMN; Jin等[28]结合羧酸酯酶2 (carboxylesterase, CE2) 易于水解酰基小、醇基大的酯类底物这一特征, 分别以萘酰亚胺和吖啶酮 (一种近红外荧光团) 为母体合成了系列酯类衍生物, 通过反复筛选获得CE2的双光子荧光探针底物NCEN和近红外探针DDAB; Lü等[29]基于葡萄糖醛酸转移酶1A1 (UDP-glucuronosyl-transferase 1A1, UGT1A1) 底物结合区多赖氨酸等碱性氨基酸这一特性, 以及该酶偏好催化多环芳烃类化合物的O-葡萄糖醛酸化反应这一特征, 以4-羟基-1, 8-萘酰亚胺为荧光团, 通过反复优化获得了UGT1A1的高特异性荧光探针底物。上述代谢酶的荧光探针底物已被成功用于复杂生物样本中目标酶的功能评价、以及代谢酶抑制剂或诱导剂的高通量筛选与评价等研究, 为生物医药相关领域提供了强有力的工具分子。因此, 未来可考虑结合CYP2J2的催化特性及其偏好底物的结构特征来设计研发CYP2J2的特异性探针底物, 并将其用于CYP2J2抑制剂的高通量筛选及CYP2J2功能异常与疾病发生发展间的关系等研究。
4 外源物对CYP2J2表达和功能的调控作用
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CYP2J2与多种疾病的发生发展存在密切的联系。一方面, 外源物质可能对CYP2J2的蛋白表达和催化功能进行调节, 破坏CYP2J2在机体中的功能平衡, 诱发疾病; 反之, 外源物质可能对CYP2J2的蛋白表达和催化功能进行调节, 恢复CYP2J2在机体中的功能平衡, 干预疾病的发生发展。因此, 明确外源物对CYP2J2的表达与功能调控对于增进CYP2J2在疾病发生发展中的认识、以CYP2J2为靶点的新药研发等方面均具有重要意义。
4.1 外源物对CYP2J2的诱导作用
目前, 对CYP2J2诱导剂的相关研究报导较少。研究发现CYP非特异性诱导剂如苯巴比妥、安妥明等均不能诱导CYP2J2表达。Lee等[30]用抗氧化剂叔丁基羟基茴香醚 (butyl hydroxy anisd, BHA) 或特丁基对苯二酚 (tertiary butylhydroquinone, TBHQ) 治疗肝癌细胞24 h后, 发现CYP2J2基因和蛋白的表达量能够增至原来的2倍。但是, 还未有针对CYP2J2诱导的更为系统的研究与报道。
4.2 外源物对CYP2J2的抑制作用
自2007年Lafite等[31]发现一种特非那定的衍生物对CYP2J2有极好的抑制作用以来, 多种化合物被研究证实会对CYP2J2产生抑制作用。Lee等[16]发现138种在售药物中就有42种对CYP2J2显现出明显的抑制作用。目前, 已被熟知的CYP2J2抑制剂有达那唑[32]、日本前胡素[30]、羟基依巴斯汀[33]、替米沙坦[34, 35]、革菌酸[36]和丹参酮IIA[37]等, 见表 3[30, 32-38]。替米沙坦和氟桂利嗪是首次发现的CYP2J2非时间依赖性抑制药物, 并且它们的选择性是其他主要CYP450成员的10倍。值得注意的是, 这些CYP2J2的抑制剂具有较强的底物依赖性。如替米沙坦虽对CYP2J2介导的阿司咪唑代谢具有显著的抑制作用, 但对CYP2J2介导的依巴斯汀和特非那定的代谢并没有抑制作用; 特非那酮可强力抑制CYP2J2对阿苯达唑、阿司咪唑和特非那定的代谢, 然而对依巴斯汀羟化的抑制作用很弱。由于CYP2J2的活性空腔与CYP3A4相似, 在近来研究发现已知的CYP2J2 抑制剂特非那酮、决奈达隆和胺碘酮同时也可作为CYP3A4的抑制剂。因此, 外源物与CYP2J2的相互作用研究仍需要进一步探索。
5 CYP2J2与疾病的关系
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根据CYP2J2在人体的分布情况及其自身和代谢产物的生理功能, CYP2J2与心血管疾病、癌症和阿尔茨海默症等疾病均息息相关。结合CYP2J2与其配体 (底物和抑制剂) 的结合特点, 一方面可以开发CYP2J2特异性探针底物检测体内CYP2J2的活性预测相关疾病, 还可以在体外合成CYP2J2抑制剂, 开发抗癌新药。
5.1 心血管疾病
CYP2J2代谢AA产生EETs, EETs在血管平滑肌细胞中能引起血管的扩张及抑制细胞迁移; 在内皮细胞中具有抗炎、促新生血管形成、促纤溶蛋白表达及调节钙离子信号通道的作用[25]。具体机制: ① EETs通过抑制核转录因子NF-κB的激活, 抑制环氧合酶-2和细胞黏附分子 (cell adhesion molecule, CAM) 的表达, 抑制单核细胞对血管壁黏附, 发挥抗炎作用[39]; ② CYP2J2通过激活蛋白激酶A打开钙激活钾通道 (血管平滑肌细胞膜电位的主要离子通道), 使包括冠脉在内的多种平滑肌细胞膜超级化, 从而抑制电压依赖性钙通道的激活及抑制钙离子内流而产生血管舒张作用; ③ 在血管床中, 一方面EETs具有促进内皮细胞生长和血管生成的作用, 另一方面EETs抑制人血管平滑肌细胞增殖。通过促进缺血组织血管生成和抑制细胞增殖发挥双重保护作用; ④ EETs还有其他多种重要的生物活性, 如影响肽类激素分泌、作用于心肌的Na+、Ca2+转运和加强心肌细胞的收缩功能[40, 41]。
首先, CYP2J2代谢AA生成的EETs在高血压、动脉粥样硬化、心肌缺血再灌注和心脏功能不全等心血管疾病的病理生理过程中发挥重要作用。其次, 2J2的基因多态性研究发现, 其G50T的突变可引起其上游启动子与转录因子的结合障碍, 由此降低自身表达, 导致血浆中EETs含量降低, 使EETs的有益作用减弱甚至消失, 由此增加冠状动脉疾病和高血压的风险[42]。即CYP2J2可以通过调控EETs的含量, 参与到多种心血管疾病中。
5.2 癌症
在食管癌、肺鳞状细胞癌、肺腺癌、肺小细胞癌、乳腺癌、胃癌、肝癌和结肠癌等癌症[43]中, CYP2J2mRNA水平和蛋白表达水平均会上调[44]。由于这一表达特性, CYP2J2成为潜在的抗癌新靶点。
5.2.1 抗癌新靶点
Let-7是最先在线虫中被发现的一类miRNA, Let-7b是Let-7家族的成员之一, 可抑制黑色素瘤细胞的生长, 是一种肿瘤抑制分子。Chen等[39]通过生物信息学分析发现当降低Let-7b会导致癌症组织中CYP2J2蛋白的表达量升高, 说明miRNA Let-7b会降低CYP2J2的表达, 抑制肿瘤生长。这证明了CYP2J2与癌症的潜在联系。日本前胡素[45]和丹参酮IIA[44]可以通过抑制CYP2J2的活性来促进肝癌肿瘤细胞的凋亡达到抗癌的效果。其原因是CYP2J2和EETS一方面通过上调抗凋亡蛋白Bcl-2、Bcl-xL的表达和抑制凋亡蛋白Bax的表达, 防止肿瘤细胞凋亡; 另一方面通过上调肿瘤转移相关基因的表达, 下调肿瘤转移抑制基因的表达, 增强肿瘤细胞的游走能力, 促进肿瘤细胞恶性增殖[31]。因此, 以CYP2J2作为抗癌新靶点下调肿瘤组织中CYP2J2的表达或抑制肿瘤组织中CYP2J2的活性均可实现抗癌效果。
5.2.2 降低抗癌药物的疗效
CYP2J2可以代谢多种外源化合物, 其中就包括伊马替尼、达沙替尼、舒尼替尼和索拉非尼等抗肿瘤药物。使肿瘤对这些药物产生耐药性, 在临床使用中达不到理想效果[3]。基于CYP2J2对抗肿瘤药物的代谢清除能力, Narjoz等[40]认为可利用现在批准药物中已知的CYP2J2抑制剂替米沙坦、氟桂利嗪等对CYP2J2的抑制作用来解决抗肿瘤药物的耐药、疗效不理想问题, 为降低肿瘤耐药性的研究工作提供了新的思路。
5.3 与阿尔茨海默症的潜在联系
近年来研究表明, 阿尔茨海默症的发生发展通常伴随着慢性炎症反应, 而炎症才是神经元死亡的根本原因。由于EETs等具有抗炎作用, 简言之, CYP2J2可通过影响EETs的生成, 对神经元的炎症状态产生重要的调节作用, 也因此参与到阿尔茨海默症的发生发展过程中[46]。
6 结语与展望
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通过对CYP2J2的持续研究, 目前已对其在人体的分布与功能有了更进一步的了解。本文通过对相关文献的汇总与分析, 明确了CYP2J2心脑血管疾病和癌症等多种疾病中的作用; 也从配体层面 (底物和抑制剂) 和CYP2J2大分子层面分别展开了综述, 加深了对CYP2J2催化及结合特征的认识。随着CYP2J2在多种疾病治疗中的应用价值和其在药物代谢中的研究价值受到越来越广泛的关注, 针对其抑制剂和探针底物的研究和研发则可能成为新的研究课题。
基金
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  • 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)
文献
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doi: 10.16438/j.0513-4870.2016-0573
  • 接收时间：2016-06-15
  • 首发时间：2026-01-14
  • 出版时间：2017-01-12
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  • 收稿日期：2016-06-15
  • 修回日期：2016-07-19
基金
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)
作者信息
    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

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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