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J Chromatogr A, 1980, 202(2): 239backs in the use of L-proline derivatives as chiral selectors [J).J245Chromatogr a,2005,1092(1):364〔26]宋爽,王金輝,等,手性高效液相圓二色檢測(cè)器( HPLC-CD)分〔37〕危風(fēng),趙迎憲.間歇色譜與模擬移動(dòng)床色譜分離奧美拉唑?qū)τ澄銎咸烟堑慕^對(duì)構(gòu)型〔J.中國(guó)現(xiàn)代中藥,2008,10(3):134:體的比較〔J〕.高?；瘜W(xué)工程學(xué)報(bào),2009,23(2):303-08〔27]朱炳輝,梁藝英,莫金垣,等.冰片中右旋龍腦及其異構(gòu)體的手(38)s. Nagamatsu,K. Murazumi,S. Makino. Chiral separation of a pharma-性毛細(xì)管氣相色譜法測(cè)定〔J].分析測(cè)試學(xué)報(bào),1999,18(4):70-eutical intermediate by a simulated moving bed process[ J). J Chro-ator A,1999,832:5565〔28]夏仕文,阮宗琴,等.手性毛細(xì)管氣相色譜法測(cè)定微生物產(chǎn)生的吲哚三甲醇的研究進(jìn)展孫超,賈玉萍,袁棟棟(山東省藥學(xué)科學(xué)院濟(jì)南250101)摘要:吲哚3甲醇(B3℃)是十字花科蔬藂中研究最多和最重要的一種抗腫瘤成分。目前的硏究表明抗腫瘤是其主要的藥理作用;但是也有硏究發(fā)現(xiàn)B3C有抗炎、抗肥胖等效果;同時(shí)以B3C為前體藥物合成的BC衍生物也有了長(zhǎng)足的發(fā)展進(jìn)步。現(xiàn)就I3C藥物開發(fā)應(yīng)用的各環(huán)節(jié)進(jìn)行綜述,使B3C的研究更加深入。關(guān)鍵詞:吲哚三甲醇;抗腫瘤;同系物中圖分類號(hào):R969;R979.1文獻(xiàn)標(biāo)識(shí)碼:A文章編號(hào):10063765(2014)474411401644中國(guó)煤化工吲哚3甲醇( Indole3 - carbinol,B3C)是十字花科蔬菜的主要成CNMHG包括 Divalent iron metaboism(mM)仕內(nèi)時(shí)一殺男募物從而在體內(nèi)發(fā)揮生物效用。作者簡(jiǎn)介:孫超,男(1986,11-)。畢業(yè)于山東中醫(yī)藥大學(xué)。學(xué)歷:目前的大量研究證明在體外、整體實(shí)驗(yàn)以及部分臨床實(shí)驗(yàn)條藥理學(xué)碩士研究生。職稱:初級(jí)。從事新藥篩選評(píng)價(jià)工作。聯(lián)系電件下,BC均可通過多種途徑發(fā)揮其抗腫瘤作用,同時(shí)B3C也話:15953115371,E-mail.cse567@126.com有抗炎、抗脂肪等藥理效用;現(xiàn)就I3C藥物相關(guān)的最新研究做16Strait Pharmaceutical Journal Vol 26 No. 7 2014綜述。臟被濃縮,由此可見肝對(duì)于B3C有很強(qiáng)的選擇性富集作用,相1B3C抗腫瘤作用反DM無此現(xiàn)象。而人類由于代謝酶類等與小鼠的不同,B3C為一種天然藥物,通過大量的體內(nèi)體外的實(shí)驗(yàn)研究B3C轉(zhuǎn)歸可能會(huì)有所不同;文獻(xiàn)表明,志愿者口服400mgB3C發(fā)現(xiàn),3C對(duì)大多數(shù)腫瘤都有良好的抑制效果,包括乳腺癌、后8h,血漿中才可檢出DM。從以上研究中,我們可以大子宮癌、前列癌、肝癌、肺癌、結(jié)腸癌、白血病等等7?？梢婓w了解B3C的吸收、分布、代謝和排泄的特點(diǎn),為以后的硏究I3C對(duì)于腫瘤有著廣泛的治療作用,并且通過大量的實(shí)驗(yàn)還鋪平道路證實(shí)B3C對(duì)腫瘤還有顯著的預(yù)防作用8,因此對(duì)B3C的深入4劑型的發(fā)展研究意義重大I3C要作為一種成熟的藥物上市,劑型的設(shè)計(jì)同樣重要2毒副作用的研究angchao luo9研究發(fā)現(xiàn)用玉米蛋白和CMCS納米粒包封的B3C作為一種天然抗腫瘤藥物,了解其副作用也不應(yīng)該B3C、DM顆粒,能夠起到緩釋控釋的作用,并且防止B3C的降忽視。研究提示4羥雌激素可以導(dǎo)致腫瘤增大或促進(jìn)其發(fā)解失效,而且比較發(fā)現(xiàn)CMCS的效果比玉米蛋白更好。展,而B3C和代謝物DM均能提高4-羥雌激素水平,并且B3C5B3C同系物的發(fā)展創(chuàng)新比DM更顯著,因此B3C口服更安全0。B3C在肝癌治療方通過對(duì)B3C深入的研究,眾多以I3C為先導(dǎo)化合物的抗面一直存在爭(zhēng)議。報(bào)道稱I3C作為一種阻斷劑,只能在癌癥胂瘤藥物也相繼被合成和發(fā)現(xiàn)。戈暢等人發(fā)現(xiàn)了一種新的啟動(dòng)階段起作用,而對(duì)啟動(dòng)后的腫瘤則作用很小,且大劑量的B3C的衍生物B3C6對(duì)宮頸癌HELA細(xì)胞有生長(zhǎng)抑制作用時(shí)對(duì)已形成的肝癌發(fā)展有促進(jìn)效應(yīng)。 Keisuke1研究 Hanh h. nguyen2)等人合成了一種B3C衍生物芐基吲哚I3C對(duì)于二乙基亞硝胺誘導(dǎo)的肝腫瘤有促進(jìn)作用,腫瘤病灶3甲基,它能夠干擾核酸生物合成,誘導(dǎo)癌細(xì)胞G1期阻滯來的大小以及發(fā)生率都有所提高,并且伴隨誘導(dǎo)CYP1A酶系表發(fā)揮抗腫瘤作用。對(duì)于3C的四聚體環(huán)狀衍生物CTet,目前達(dá)增強(qiáng),以及提高接下來的氧化應(yīng)激反應(yīng);并且過多的3C攝取得了大量的研究成果。 Mauro De santi2研究發(fā)現(xiàn)在MCF入會(huì)提高AhR活性,上調(diào)微粒體的活性氧,從而導(dǎo)致氧化還7和 MDA-MB231兩種細(xì)胞中,CIet能夠通過p2l/CDKN1A原的不平衡,使肝細(xì)胞增殖促進(jìn)肝腫瘤的發(fā)生。 James研的過度表達(dá)來抑制細(xì)胞的增殖,在移植了MCF7細(xì)胞的裸鼠究發(fā)現(xiàn)50mg·kg劑量B3℃能夠使大鼠肝細(xì)胞可逆性肥大,腫瘤模型中,Cret也能夠抑制抑制MCF刁的增殖,并且對(duì)體P450酶系活性增強(qiáng),而DM無此現(xiàn)象。B3C對(duì)特定人群可能重和血液沒有副作用。Glwi23)也發(fā)現(xiàn)在MCF7、MDA會(huì)產(chǎn)生特殊的不良反應(yīng),通過 You- Yan3研究發(fā)現(xiàn)B3C能MB231兩種乳腺癌細(xì)胞中,CTt能夠激活內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)夠提高大鼠的CYAⅠ和P糖蛋白的水平,從而能夠增強(qiáng)煙誘導(dǎo)細(xì)胞自噬,從而使癌細(xì)胞死亡。對(duì)于I3C的衍生物OSU-草煙導(dǎo)致的胎兒增長(zhǎng)緩慢,這對(duì)于妊娠期的婦女患者用藥很A9,也取得了不少的研究成果。Weng23發(fā)現(xiàn)在離體的乳有意義。腺癌細(xì)胞培養(yǎng)中,OSU-9能夠通過阻斷Akt-NF+B的傳導(dǎo)作為研究階段的3℃來說,了解其毒理特點(diǎn)尤為重要。通路和應(yīng)力感應(yīng)信號(hào)來抑制乳腺癌細(xì)胞的增殖,并且作用強(qiáng)BOYLE對(duì)B3C做了 Fisher34大鼠和B6C3F1小鼠灌胃亞于B3C;oSU-9對(duì)于口腔鱗狀細(xì)胞癌細(xì)胞SCC4、SCC15和慢性毒理學(xué)以及慢性毒理實(shí)驗(yàn)的中期剖殺檢測(cè)的硏究,劑量sC?2095同樣有顯著的抗增殖作用,并且對(duì)正常的口腔角質(zhì)大于150mg·kg時(shí),大鼠出現(xiàn)劑量相關(guān)的十二指腸、空腸以細(xì)胞不敏感,療效明顯強(qiáng)于I3C。Omar發(fā)現(xiàn)OsU-9抗肝及淋巴結(jié)的淋巴管擴(kuò)張;觀察到腸固有層、乳糜管以及巨噬細(xì)癌作用也是通過干擾 Akt-NF≮B信號(hào)通路來發(fā)揮的,對(duì)于胞都有細(xì)胞外脂肪的積累;劑量大于1875mg·kg時(shí),肝Hep3B,Hu7,PC5HCC腫瘤細(xì)胞的抑制作用是13C的100CYPIAⅠ和 CYPIA2活性上調(diào)且有劑量正相關(guān),肺CYPA1活倍;對(duì)于接種了Hep3B肝癌細(xì)胞的裸鼠,給OSU-925和性也上調(diào)但是有明顯的雌雄差異,雄性在75mg·kg時(shí)才50mgkg-56天,抑制率達(dá)到67%和80%,并且沒有觀察到有顯著性,B6C3F1小鼠在在250mg·kg時(shí),無組織損傷變毒性發(fā)生以及肝代謝的變化,在腫瘤內(nèi)部與 Akt-NF*B信號(hào)化,肝CYP酶系的變化與大鼠相似,但是劑量相關(guān)性不強(qiáng)。通路相關(guān)的生物標(biāo)記物發(fā)生明顯變化。有此可見OSU-9的I3C的初步毒性研究還不足以深入了解13℃的毒性,犬類和抗腫瘤方面的效果及安全性都強(qiáng)于B3C,在抗腫瘤方面潛力靈長(zhǎng)動(dòng)物的毒理探索還有待開展巨大。LTr4作為BC的體內(nèi)衍生物,Chmg2)研究發(fā)現(xiàn)Lr3藥代動(dòng)力學(xué)的探索1對(duì)MCF刁、 MDA-MB=231均有抑制增殖作用,并且對(duì)雌激素B3C在消化道的酸性環(huán)境中會(huì)形成多種縮聚物,其中以受體有拮抗作用,而對(duì)芳烴受體有一定的激動(dòng)作用。 SarahDM尤為重要。 ANDERTON通過給雌性CD小鼠喂飼M.Jump3研究發(fā)現(xiàn)B3C的N原子取代烷氧基后的衍生物活200mg·kg'BC,3C約lh內(nèi)即可在血漿和組織中被迅速吸性顯著增強(qiáng),并且碳鏈越長(zhǎng)活性越強(qiáng),而C3羥甲基基團(tuán)是收和清除:15min時(shí),Ⅰ3C主要在肝臟和腎臟濃縮,此時(shí)其在BC中國(guó)煤化工性消失;為BC衍生物的心、肺、腦中的濃度也達(dá)到最高值,肝中B3C最高濃度值約為研究CNMHGIo Mazzei合成了16種血藥濃度6倍,這與其促進(jìn)肝癌的副作用可能有關(guān);經(jīng)口給予BC不對(duì)標(biāo)業(yè)中基衍生物,經(jīng)過MCF和 MDA-MB231兩種I3C15min血漿和組織中即可檢測(cè)到DIM,且可持續(xù)存在至少乳腺癌細(xì)胞篩選發(fā)現(xiàn)3-7′乙酰氧基4′甲基香豆素8′基)6h,可見DIM的半衰期明顯高于B3C;肺中DIM濃度最高可達(dá)甲基2甲基吲哚活性最強(qiáng),將成為有前途的抗癌細(xì)胞增殖的血漿濃度的14倍并可持續(xù)lh以上,DM也主要在腎、肺和心藥物。Hung研究發(fā)現(xiàn)BC的新的衍生化合物SK28能夠海峽藥學(xué)2014年第26卷第7期擾亂FAK/Pali途徑,誘導(dǎo)癌細(xì)胞凋亡,也能夠抑制裸鼠移〔3〕 GARIKAPATYⅤP, ASHOK B T, CHEN Y G,eta.Aniτ ircinogente植腫瘤的生長(zhǎng)。通過眾多BC衍生物的合成以及相互間的比nd anti-metastatic properties of indole-3-carbinol in prostate cancer較,一定能夠找出比3C更有效更具安全性的衍生物。6I3C其他藥理作用的發(fā)現(xiàn)[4)SHUKLA Y, KALRA N, KATIYAR S, et al. Chemopreventive effect ofB3C作為一種天然藥物,不僅具有良好的抗腫瘤作用,在indole 3-carbinol on induction of preneoplastic altered hepatic foci其他方面的藥理作用也漸漸的被發(fā)現(xiàn)和重視。 McLindon(31[] Nutr Cancer, 2004, 50: 214-220等觀察了每天服用375mg3CSLE(紅斑狼瘡)女性患者的效mice應(yīng),結(jié)果顯示尿2OH雌酮/16αOH雌酮比值增大、SLE活動(dòng)post-initiation or progression phase of lung tumorigenesis[J ].Cance度指數(shù)降低,說明該效應(yīng)可能得益于B3C的抗雌激素效應(yīng)。Lett. 2011 December 1, 311(1): 57-65.I3C還可以通過抑制TGF書/smad信號(hào)通路來減輕博萊霉素(6) E Ann hudson et al. Growth-inhibitory effects of the chemopreventive致小鼠肺纖維化,可作為一種輔助用藥預(yù)防肺部的損傷32Agrawal3研究發(fā)現(xiàn)BC能夠抑制環(huán)磷酰胺誘導(dǎo)的骨髓細(xì)胞ne putrescine in the SW480 colon tumour cell line BMC [J]. Cane-染色體的變異?？梢源_定BC在化療過程有一定的扶正效2003,3果,降低機(jī)體的損傷。SUNG3等研究發(fā)現(xiàn)B3C對(duì)革蘭氏陰7) Yoshiaki Machijima, hie Ishikawa et al anti-adult t-cell leukemia/性菌作用較弱是由于革蘭氏陰性菌細(xì)胞膜外的脂多糖屏障造ymphoma effects of indole-3-carbinol[ J]. Retrovirology. 2009, 6: 7成的,而通過氨芐西林對(duì)細(xì)胞膜的破壞,BC能發(fā)揮其抗菌作(8 ashwOOD,. u The disposition and metabolism2m用,與氨芐西林發(fā)揮協(xié)同作用。B3C同樣具有抗真菌作用,能methylimidazo-[4, 5] quinoline in the F344 rat at high versus low do-夠通過羥基自由基的累積、細(xì)胞色素C的釋放以及激活metaof indole-3-carbinol( J). Food and Chemical Toxicology. 2003, 4111854192caspases來好誘導(dǎo)白色念珠菌的凋亡”。BC還可以通過誘導(dǎo)(9)Y.4 Heet al. Indole.- arbinol as a Chemopreventive Agent in2A-肝星型細(xì)胞的凋亡,改善大鼠的肝臟纖維化。 Youngshimmino-H-methyl-6-phenylimidazo( 4, 5-b ]pyridine( PhIP)CarcinogeneChoi3研究發(fā)現(xiàn)B3C作用與飼喂高脂飼料的雄性C57BL/6 N sis. Inhibition of PhIP主 dnA Adduct f, Acceleration of phip小鼠,能夠通過 SIRTI-AMPK信號(hào)系統(tǒng)的上調(diào)來阻止小鼠肝Metabolism, and Induction of Cytochrome P450 in Female F344 Rats臟的脂肪樣變性。 Jie ping等研究發(fā)現(xiàn)B3C能夠降低NAD-[J]. Food and Chemical Toxicology. 2000, 38: 15-23PH氧化酶活性和活性氧的生成,以及p38MAPK的磷酸化,(10R0 GanE G, BADAWIA F, DEVANESAN P D, et al. relative im從而抑制肝星型細(xì)胞HSC的增殖?？梢夿3C對(duì)慢性肝病的balances in estrogen metabolism and conjugation in breast tissue of治療還是具有可觀潛力的。 Chan發(fā)現(xiàn)B3C作用于women with carcinoma potential biomarkers of susceptibility to cancer〔J. Carcinogen,2003,24:697-702.CS7BL6雄性小鼠,在其脂肪組織中能夠阻滯巨噬細(xì)胞的浸11) Chang x,ToJC, Hong C,tal.3,3 -Diindolylmethane inhibits an-潤(rùn);巨噬細(xì)胞和脂肪細(xì)胞共同培養(yǎng)的體系中,I3C能夠減少亞giogenesis and the growth of transplantable human breast carcinoma in硝酸鹽產(chǎn)物的量以及下調(diào)Ⅱ6的表達(dá);而在脂肪細(xì)胞單獨(dú)培athymic mice[ J]. Carcinogenesis, 2005, 26(4): 771-778養(yǎng)的體系中,B3C也能夠抑制脂質(zhì)在細(xì)胞內(nèi)的積累。Jumn(12)k. Shimamoto et al Relationship between CYPIA induction by indole-Jiang等研究發(fā)現(xiàn)I3C能夠通過阻斷巨噬細(xì)胞TRF依賴的3-carbinol or flutamide and liver tumor-promoting potential in rats信號(hào)途徑來抑制細(xì)菌脂多糖引起的炎性反應(yīng),抑制急性肺損Arch[J. Toxicol.2011,85:11591166傷小鼠免疫細(xì)胞和促炎性細(xì)胞因子的浸潤(rùn)。所以BC有良好13)K. Shimamoto et al. Indole3 carbinol enhances oxidative的抗炎作用以及與肥胖相關(guān)疾病的預(yù)防。 Hongjing Guansponses resulting in the induction of preneoplastic liver cell lesions in等研究發(fā)現(xiàn)在大鼠血管損傷后,B3C能夠通過對(duì)Akt/GSK3βartial hepatectomized rats initiated with diethylnitrosamine [J]途徑的抑制作用,抑制大鼠血管平滑肌細(xì)胞的增殖以及新生Toxicology.2011,283:109117血管內(nèi)膜的增生,具有治療血管增生性疾病的潛力[14)J. A. Crowell et al. Indole-3-carbinol, but not its major digestive prod7結(jié)語ct3, 3 diindolylmethane, induB3C通過各種作用機(jī)制發(fā)揮了較強(qiáng)的腫瘤化學(xué)預(yù)防效應(yīng)cytochromes P450 Toxicology and Applied (J]. Pharmacol-和抗腫瘤效應(yīng),并且未見即時(shí)和遠(yuǎn)期的毒副作用;而隨著對(duì)gy.2006,211:115123I3C藥學(xué)各方面的認(rèn)識(shí)加深,B3C的衍生物的研究也得到了長(zhǎng)[15JY.E. Yan et al. 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Unsymmetrical methylene derivatives of indoles24:626更正中國(guó)煤化工本刊2014年第5期(總第172期)第80~81頁(yè)刊登第CNMH尼與七氟醚靜吸復(fù)合喉罩通氣全麻在輸卯管結(jié)扎術(shù)的應(yīng)用”中正文擬仃物卯結(jié)扎術(shù)病人36例”應(yīng)改為“擬行輸卵管結(jié)扎術(shù)病人30例”,系印刷錯(cuò)誤,特此更正,并向作者致歉。