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紫苏醇的研究进展

2016-03-09黄杰秋朱秋劲茅林春罗自生

贵州农业科学 2016年9期
关键词:紫苏母细胞胶质

黄杰秋,朱秋劲,2,3*,茅林春,罗自生

(1.贵州大学酿酒与食品工程学院,贵州 贵阳550025;2.贵州省农畜产品贮藏与加工重点实验室,贵州 贵阳550025;3.国家牛肉加工技术研发分中心,贵州惠水550600;4.浙江大学馥莉食品研究院,浙江杭州310058)

紫苏醇的研究进展

黄杰秋1,朱秋劲1,2,3*,茅林春4,罗自生4

(1.贵州大学酿酒与食品工程学院,贵州 贵阳550025;2.贵州省农畜产品贮藏与加工重点实验室,贵州 贵阳550025;3.国家牛肉加工技术研发分中心,贵州惠水550600;4.浙江大学馥莉食品研究院,浙江杭州310058)

紫苏醇是带有香气的单萜类天然活性物质,在医药、食品和化妆品等行业具有广阔市场空间和研究价值;在发达国家,紫苏醇已广泛用于胶质母细胞瘤、胰腺癌、肺癌、皮肤癌、乳腺癌等的临床治疗,近几年其抗癌机制研究取得重大突破。为紫苏醇的进一步研究提供参考,从紫苏醇的获取途径、功能与应用方向等方面进行综述,并对其加工与应用进行了展望。

获取方法;功能;应用;紫苏醇

紫苏醇是单萜类的天然产物,主要以游离态或酯的形式天然存在于紫苏叶、柑桔、樱桃、薄荷、樱桃、香柠檬、姜草及薰衣草等多种植物中,是植物甲醛戊酸代谢途径产生的单萜化合物[1-3]。紫苏醇为无色较粘稠液体,气味略带木香和花香[4]。其性质稳定,耐热耐酸,不易挥发,溶于甲醇、乙醇和乙腈等有机溶剂[5],可从天然植物精油中分离获得,现有的紫苏醇大多采用天然存在的单萜化合物为起始原料,经合适的化学或生物转化法获得[6]。

紫苏醇有较高的抗肿瘤活性[7],受到国内外学者高度关注。在美国等发达国家,紫苏醇早已进入临床研究阶段[8],近年来对紫苏醇的抗癌机制研究取得很大突破[9-12],在胶质母细胞瘤、皮肤癌、胰腺癌、肺癌、肝癌、乳腺癌、前列腺癌和淋巴癌等疾病治疗中具有较大功效。临床应用数据表明,口服较大剂量紫苏醇后对患者有副作用,会导致肠胃不适,呕吐和腹泻[7]。经过多年临床实践,鼻腔靶向给药,能够绕过血脑屏障快速到达中枢神经系统,大大降低系统性污染和减少副作用[12]。另外,紫苏醇还被广泛应用于食品、保健品及香精香料领域。为全面系统地认识和了解紫苏醇,笔者对紫苏醇的获得途径、功能及药理机制研究进展进行综述,旨在为紫苏醇的应用及后续研究提供参考。

1 紫苏醇的获取途径

1.1 生物转化

合成生物学和代谢工程技术迅速发展,为改造目标分子的天然生产物种或设计异源生产途径提供了可能。紫苏醇可通过柠檬烯、α-蒎烯、β-蒎烯等经合适的生物转化法获得。Alonso利用大肠杆菌的代谢柠檬烯生产紫苏醇,大肠杆菌不同的甲羟戊酸途径和柠檬烯合酶生产的柠檬烯耦合细胞色素P450,柠檬烯羟化产生紫苏醇,其产量约100mg/L[13]。宋叶华等[14-15]分别成功地利用酿酒工程酵母生产香紫苏醇。构建酿酒酵母生产紫苏醇的工程途径值得尝试。柠檬烯的微生物转化所得到的产物具有区域选择性和立体选择性,且微生物转化反应操作简单、条件温和、无毒及环境友好。

1.2 其他方法

紫苏醇可从天然植物精油中分离获得,如采用有机溶剂或超临界CO2萃取,但因含量太低分离不易导致成本过高[16]。孔江波等[17]利用瑞士Sulzer公司金属丝网填料制成的中试装置,通过精馏方式提纯紫苏醇,其含量及色泽均较以前的方法有较大改进。

2 紫苏醇的功能

2.1 抗胶质母细胞瘤

2.1.1 鼻腔靶向给药治疗 Fonseca等[18]先后4年将紫苏醇以440mg/d和533.6mg/d鼻腔给药治疗不同复发性恶性神经胶质瘤,成人患者未表现出副作用。高浓度的紫苏醇鼻腔给药成功地治疗了1例复发胶质母细胞瘤,期间偶尔会引起鼻子酸痛但很少引起鼻出血。紫苏醇鼻腔靶向给药绕过血脑屏障,有效浓度在脑组织中维持的时间长度充足,治疗脑部肿瘤效率较高,而且没有副作用[19]。

2.1.2 药理机制 Fonseca等[20]将紫苏醇以鼻腔靶向给药的方式,对Ⅰ/Ⅱ期临床试验执行标准治疗后复发恶性神经胶质瘤的患者进行治疗时发现,该方法能明显抑制肿瘤扩散,其药理机制是紫苏醇抑制了小G蛋白的合成,激活Ras途径。后期临床研究发现,大脑神经胶质瘤细胞在不同的微环境之间的相互作用可以影响神经胶质瘤细胞的肿瘤生物学行为[21]。后期研究发现糖原合酶激酶和细胞外信号调节激酶与紫苏醇激活癌细胞凋亡机制相关[22]。Silva等[23]对95例复发性恶性神经胶质瘤中Ⅰ/Ⅱ期患者进行紫苏醇鼻腔给药,紫苏醇能提高GSTM1基因缺失和GSTT1基因缺失患者的存活率。Chen等[24]进行体内体外试验发现,紫苏醇抑制胶质母细胞瘤增殖的机制是抑制Na/K-ATPase酶活性,加速癌细胞凋亡。

2.1.3 复发胶质母细胞瘤的治疗 紫苏醇吸入化疗法能暂缓胶质母细胞瘤生长,大约8个月后肿瘤继续生长。Fonseca等[19]对人类胶质母细胞瘤细胞A172r进行培养时发现,A172r细胞表达出一系列耐药蛋白质,这些蛋白促进细胞增殖,抑制Ras途径;另外,Fonseca等报道,一位37岁的复发胶质母细胞瘤患者,接受紫苏醇鼻腔给药单一化疗方式(268mg/d)治疗8年,未发生病变。紫苏醇鼻腔给药单一化疗能否有效抑制长期复发性脑胶质瘤还不能确定。Cho H-Y等[25]对新药NEO214(咯利普兰共轭紫苏醇)治疗多形性胶质母细胞瘤进行评估,NEO214显著多形性胶质母细胞瘤死亡受体DR5的表达,癌细胞死亡率超过90%。Silveira等[26]对83例复发性神经胶质瘤在Ⅰ/Ⅱ期临床试验结果进行统计发现,神经胶质瘤的多态性与EGF循环水平基因型有相关性。

2.2 抗肺癌

Fischer[27]研究热休克蛋白HSP70和紫苏醇对肺腺原癌基因k-ras表达的影响发现,紫苏醇能影响ERK通路,从而抑制人类肺癌细胞。Yeruva[5]研究发现,紫苏醇及其代谢物紫苏酸(PA)能抑制肺癌细胞A549和H520增殖。Imamura等[28]研究发现,紫苏醇显著抑制小鼠过敏性气道炎症指标如气道嗜酸性粒细胞,显著抑制胸淋巴结细胞因子的产生。Salazar等[29]对紫苏醇鼻腔给药后的老鼠的肺、脾脏和大脑等进行细胞毒性试验,紫苏醇鼻腔给药能激活支气管肺泡先天免疫系统的淋巴组织。紫苏醇作为药物能影响肺组织的病理过程,其可能具有预防或治疗肺部疾病(如哮喘)的作用。

2.3 抗乳腺癌

乳腺癌是美国女性癌症死亡的第二大原因。传统治疗方案治疗乳腺癌有不同的副作用,为减轻副作用,科研人员采用植物化合物对肿瘤细胞进行化疗。Bailey[30]对乳腺癌患者进行一期口服紫苏醇治疗试验发现,紫苏醇能抑制癌细胞生长。而二期口服紫苏醇(1 200mg/d)临床试验却对治疗难以转移的乳腺癌没有效果。Yeruva L[31]用紫苏醇茉莉酮酸酯与顺铂协同治疗,能降低线粒体膜电位,阻止G0/G1期的细胞分化,促使细胞凋亡。

2.4 治疗肾脏疾病

Jahangir[32]用紫苏醇治疗肾毒性早期肿瘤的老鼠发现,黄嘌呤氧化酶和鸟氨酸脱羧酶活性均下降,胸腺嘧啶核苷也显著减少,血清毒性标记血液尿素氮和肌酐下降。Garcia等[33]研究表明,紫苏醇抑制豚鼠的肾脏和大脑以及人类胶质母细胞瘤细胞系的Na/K-ATP酶活性。抑制作用表现在对肾脏酶表达的高度选择性,对紫苏醇抗肿瘤活性与Na/KATP酶有一定相关性。

2.5 抗胰腺癌

Wiseman[34]研究发现,紫苏醇、金合欢醇和香叶醇能阻滞胰腺癌细胞G0和G1期,从而抑制癌细胞增殖。Matos[35]结合紫苏醇对胰腺癌患者化疗后的相关指标获得预测胰腺癌细胞凋亡的模型。Lebedeva[36]用膳食补充紫苏醇加上基因疗法治疗胰腺癌,能有效抑制IL-24蛋白质的产生,从而抑制胰腺癌细胞生长。Azimi[37]建议从天然产物中寻找新的药物制剂探索天然活性物质间的协同效应,是寻找新的有效药物治疗胰腺癌方法。Sarkar等[38]使用CTV-M7病毒改性嵌入mda-7/IL-24基因与紫苏醇相结合能有效加速胰腺癌细胞凋亡。

2.6 抗皮肤癌

局部涂抹紫苏醇能抑制紫外线(UV)诱导的皮肤致癌。Stratton[39-40]随机挑选正常健康的皮肤与很少或没有晒伤和有皮肤癌历史的人进行局部涂抹紫苏醇精油试验,第一阶段试验表明,人的皮肤对紫苏醇膏耐受性良好,没有严重的皮肤毒性、系统性毒性或组织病理学观察异常;第二阶段试验表明,紫苏醇能抑制黑色素肿瘤细胞基因的表达或细胞增殖,且适度涂抹紫苏醇能修复被阳光晒伤的皮肤,改善表皮。Chaudhary[41]研究结果表明,紫苏醇化疗能有效抑制小鼠白化病,机制可能是由于抑制氧化应激反应,抑制细胞增殖通路,诱导小鼠皮肤肿瘤中细胞凋亡。D'Alessio等[42]用紫苏醇分别治疗皮炎和机械皮肤损伤的模型小鼠表明,紫苏醇有显著抗炎效果,促进小鼠皮肤炎症的消褪,减少系统性的内皮细胞因子的产生,有效修复表皮屏障。

2.7 治疗白血病

Gómez[43]的体外实验及Ⅰ、Ⅱ期试验表明,紫苏醇有抗淋巴癌作用。己酮可可碱与紫苏醇结合对白血病骨髓单核细胞U93的放大抗肿瘤试验表明,2种化合物的存在导致癌细胞的凋亡,引起线粒体膜电位的变化,治疗癌症患者有临床意义。Clark[44]测试了紫苏醇是否会抑制原癌基因的表达发现,紫苏醇对慢性粒细胞白血病分裂期没有影响,原癌基因Bcr/Abl的RNA和蛋白质的表达也并没有受到影响。相反,紫苏醇能保护Bcr/Abl基因的转录。

2.8 其他

Khan[45]成功地证明了紫苏醇不但具有抗氧化活性,能明显改善乙醇诱导急性肝损伤,还可以调节TNF-a释放,激活NFκ-B。治疗后的老鼠血清中,天冬氨酸氨基转移酶、丙氨酸转氨酶和乳酸脱氢酶和肝丙二醛显著增加。Sultan等[46]评估紫苏醇对化学诱导的肝癌老鼠的治疗效果发现,紫苏醇抑制了鸟氨酸脱羧酶和胸苷磷酸化酶活性,有效防止氧化应激,并降低肿瘤发生率。D′Alessio等[47]对老鼠灌胃D-柠檬烯和紫苏醇,然后将老鼠控制在紧张状态,能有效缓解老鼠的应激状态,有助于缓和副交感神经的平衡。Bound等[48]报道,紫苏醇对黄曲霉毒素有一定抑制作用。

3 紫苏醇的应用领域与展望

3.1 在医药方面的应用

在医药领域,紫苏醇主要用于癌症的化疗治疗。紫苏醇口服有一定副作用,对于治疗神经中枢、呼吸道疾病,建议采用鼻腔靶向给药。目前,紫苏醇内服注射药剂主要是胶囊、紫苏醇亚微乳和紫苏醇壳聚糖亚微乳,外用多采用紫苏醇精油及紫苏醇软膏。Farazuddin等[49]制备紫苏醇PLGA微粒,其释放性持续时间久,对动物皮肤乳头瘤治疗功效显著。

临床上紫苏醇常与其他药物联合组成协同抗癌制剂、与其他化合物耦合共轭形成新的化合物。目前紫苏醇的衍生物研发也取得较多成果,如紫苏醛环氧化物,是紫苏醇的一种衍生物,用其对老鼠的肝脏、脾脏、肾脏和血液毒理学效应试验,具有显著的抗肿瘤活性,没有系统性毒性。同时发现,紫苏醛及其环氧化物对癌细胞的细胞毒性比紫苏醇高[50]。我国研究人员合成了一个新兴药物紫苏醇替莫唑胺,用于治疗鼻咽癌。研究报道,新药NEO214(咯利普兰共轭紫苏醇)能显著增加多形性胶质母细胞瘤死亡受体DR5的表达[51]。己酮可可碱与紫苏醇结合,可导致白血病骨髓单核细胞显著凋亡。紫苏醇与基因疗法联合是比较前沿的治疗方法[10]。

3.2 在食品及化妆品等行业的应用

紫苏醇用于仿制柑橘、香草、水果型食用香精和日化香精或制成乙酸酯,用来制作保健食品,是一种非常好的食品添加剂。化妆品如薰衣草等精油中都含有紫苏醇。构建酿酒酵母生产香紫苏醇的工艺已经相对成熟,相信紫苏醇酿酒酵母也可较快地构建出来。

3.3 展望

紫苏醇是一种有特殊香味、无毒无害、能抑菌、抗氧化、抗应激及抗癌的天然活性成分。构建合适的酿酒酵母或其他工程菌生产紫苏醇将成为其主要生产途径。开发新型的营养功能性紫苏醇休闲食品、保健品、香料、调味品、酒水及饮料等将具有很大市场空间。紫苏醇对皮肤组织有修复作用,能抑制紫外线引起的皮肤癌,将紫苏醇添加到精油、防晒霜和修复液等化妆品中,对护肤品行业发展有一定经济价值。紫苏醇对多种癌症治疗都有显著逆转作用,因此,研究紫苏醇与其他抗癌天然活性物质的协同抗癌机理及紫苏醇抗癌药物的代谢动力学,将对癌症治疗及医学进步具有重要的现实意义。

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(责任编辑:姜 萍)

Advances in Perillyl Alcohol

HUANG Jieqiu1,ZHU Qiujin1,2,3*,MAO Linchun4,LUO Zisheng4
(1.CollegeofLiquorandFoodEngineering,GuizhouUniversity,Guiyang,Guizhou550025;2.KeyLaboratoryof AgriculturalandAnimalProductsStoreandProcessingofGuizhouProvince,Guiyang,Guizhou550025;3.Branch ResearchCenterofNationalBeefProcessingTechnology,Huishui,Guizhou550600;4.FuliInstituteofFood Science,ZhejiangUniversity,Hangzhou310058,China)

Perillyl alcohol,a natural and active monoterpene,has comfortable and special aroma and stable physicochemical property.It is widely used in pharmaceutical,daily chemical and food industry,which has great research value and future application.In developed countries,perillyl alcohol has been used extensively in clinical treatment of glioblastoma,pancreatic cancer,lung cancer,skin cancer and breast cancer.It acquired many major breakthroughs in antitumor mechanism.The obtaining method,function and application of perillyl alcohol were summarized,and the processing and application were proposed as well.

perillyl alcohol;acquisition method;function;application

S38

A

2016-06-12;2016-08-30修回

浙江大学馥莉食品研究院资助项目“贵州植物资源利用”(700952142203)

黄杰秋(1991-),女,在读硕士,研究方向:食品营养与安全。E-mail:1575602009@qq.com

*通讯作者:朱秋劲(1969-),男,教授,博士,从事畜产品加工与贮藏研究。E-mail:qiujin-z@hotmail.com

1001-3601(2016)09-0395-0109-05

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