修回日期: 2008-04-30
接受日期: 2008-05-05
在线出版日期: 2008-07-08
苷类中药生物利用度低, 摄入后需经肠道细菌代谢成苷元而发挥其药理作用. 由于人群中不同个体的肠道菌群对同一苷类中药成分具有不同的生物转化作用, 不同菌株的生物转化底物及代谢产物亦不相同, 造成不同个体苷类中药的药效差异. 因此, 筛选出具有生物转化苷类中药活性的特异性肠道细菌菌属和菌株, 将之与苷类中药同时摄入, 将有助于消除苷类中药在人群中应用的个体差异. 本文就苷类中药生物转化与肠内吸收的关系、特点及应用的研究进展加以综述.
引文著录: 李咏梅, 李晓眠, 朱泽. 苷类中药肠道细菌生物转化的研究进展. 世界华人消化杂志 2008; 16(19): 2144-2148
Revised: April 30, 2008
Accepted: May 5, 2008
Published online: July 8, 2008
The bioavailability of glycosides from Chinese medicinal is low. Glycosides are metabolized into aglycons in presence of intestinal bacteria before they are absorbed. As there is individual difference in bioavailability of glycoside, and there are also difference in substrate and metabolite among bacterial strains, drug effect difference is thus observed among individuals. Therefore, screening the specific bacterial genus or strains and using them as additive of glycosides should remove individual difference in bioavailability of glycosides. This article reviewed the recent advances in relationships, features and application in biotransformation of glycosides from Chinese medicinal.
- Citation: Li YM, Li XM, Zhu Z. Advances in biotransformation of glycosides from Chinese medicinal by human intestinal bacteria. Shijie Huaren Xiaohua Zazhi 2008; 16(19): 2144-2148
- URL: https://www.wjgnet.com/1009-3079/full/v16/i19/2144.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v16.i19.2144
苷(glycosides), 又称配糖体, 是由糖或糖的衍生物, 如氨基酸、糖醛酸等与另一非糖物质通过糖的端基碳原子连接而成的化合物, 其中非糖部分称为苷元(aglycone)或配基. 苷的药效由苷元决定的, 苷元与糖结合成苷后, 其理化性质改变, 影响了药代动力学过程、药效强度和持续时间. 药代动力学研究证明, 苷类成分肠道内难以吸收、生物利用度低、肠内滞留时间较长而易受到肠道菌群的作用. 苷经肠道细菌代谢后被水解, 生成苷元而发挥其药理作用[1-4]. 因此, 将苷类中药转化成苷元, 提高其生物利用度的研究是有效提高其药效的一个重要方法, 此方面研究已经成为国内外研究热点.
目前研究的转化方法主要有化学法, 如日本Hayashibara橙皮研究所[5]采用糖基化方法制成糖基化橙皮苷. 在强烈的化学反应中苷类物质的结构和构型会发生改变, 导致其产物不稳定或药效消失. 酶解法, 如瑞士雀巢研究中心[6]采用酶修饰方法, 用橙皮苷酶水解橙皮苷获得橙皮素-7-糖苷. 但酶解法转化苷类中药是以苷提取物为作用底物, 使用糖苷水解酶作为催化剂, 工艺过程复杂, 不利于工业化生产. 生物转化法的本质是由微生物产生的一种或几种特殊胞外或胞内酶作为生物催化剂对外源性底物进行的一种或几种化学反应. 生物转化既可增加目标产物产量, 克服化学合成的缺点, 又因其大多数是在室温、中性环境中作用, 减少了产物分解、异构、消旋和重排反应, 因此具有位置选择性和立体选择性, 和无毒、无污染、低成本、高收率、环境友好等特点[7-8]. 本文将围绕苷类中药生物转化与肠内吸收的关系、特点及应用加以综述.
生物转化也称生物催化(biocatalysis), 是指利用酶或有机体(细胞、细胞器)作为催化剂实现化学转化的过程, 是生物体系(包括细菌、真菌、植物组织、动物组织培养体系或生物体系)的酶制剂对外源性底物进行结构性修饰所发生的化学反应. 微生物因其培养简单、种类繁多、酶系丰富而成为生物转化中最常见的有机体[9-12].
苷类中药生物利用与肠道细菌的相互作用已经被很多学者所重视, 做了大量的工作. 大多数中药是通过口服在消化道吸收发挥局部或全身作用, 因此脂溶性扩散是药物在消化道内跨膜转运的主要方式. 但是大多数苷因亲脂性低而不易转运到靶部位, 造成消化道对苷类成分吸收较差、较慢. 而苷由特异肠道菌群分泌的酶水解为苷元后脱去糖基, 极性减小, 脂溶性增加, 使苷元在人体内吸收快于苷的吸收. 苷元能迅速经小肠吸收入血液循环, 较快达到所需血药浓度, 发挥其药效作用[13]. 如芍药苷具有抗炎、镇痛、免疫调节及抗原发性肝癌等作用[14-16], 而其口服吸收率极低. 经口服摄入的芍药苷需在肠道细菌分泌的β-葡萄糖苷酶和酯酶的催化下转化成其相应苷元Paeonimetabolin[17]才能发挥生理作用. 在Caco-2细胞上的转运研究[2]亦发现芍药苷的生物利用度比其苷元低40倍.
人体肠道内存在大量微生物[18], 约占人体微生物总量的80%, 其中厌氧菌为需氧菌的100-1000倍. 肠道正常微生物群类型包括三类: 一是致病性类型, 主要包括韦荣球菌、葡萄球菌、变形杆菌及假单胞菌, 菌量少, 在病理条件下可大量繁殖而致病. 二是互生性类型, 主要包括双歧杆菌、类杆菌、真杆菌和消化球菌, 数量多, 具有维生素合成、生物拮抗、促进蛋白质消化吸收和免疫刺激等生理作用. 三是中间性类型, 主要包括乳杆菌、大肠埃希菌、链球菌和韦荣球菌. 数量介于前两者之间, 既有生理作用, 也有致病作用. 健康人肠道菌群的平衡是相当稳定的. 内因或外因, 如感染、胃肠功能紊乱、外科手术、精神应激、使用抗菌素、衰老等原因均会影响肠道菌群的平衡, 但造成的变动是非特异性的. 如我国糖尿病患者调查发现, 糖尿病患者肠道菌群紊乱, 肠道内互生性类型细菌显著减少[19]. 由于粪便中含有肠道内所有菌株, 所以苷类中药肠道细菌生物转化的研究工作常以新鲜粪便为标本, 从中筛选具有生物转化苷类中药能力的特异性菌株.
研究发现同一种苷类中药不同个体间的药效存在差别. 苷类中药体内代谢研究[20]发现人群中不同个体肠道菌群对同一苷类中药成分具有不同生物转化作用. 大豆异黄酮是目前研究较多的保健中药苷类, 对于与激素有关的癌症(前列腺癌和乳腺癌)[21-23]、心血管疾病[24-26]和骨质疏松[27-28]等疾病均有预防作用. 大豆异黄酮中含量占优势的是大豆苷和染料木苷两种. 肠道细菌对大豆异黄酮在宿主体内的降解和利用起着关键作用[29]. 大豆苷体内代谢研究发现, 其被肠道细菌代谢为雌马酚和O-脱甲基安哥拉紫檀素(O-demethylangolensin, ODMA)[30-34], 但人群中大约只有1/3到1/2人摄入大豆苷后体内能生成雌马酚[35-36]. Hedlund et al[37]调查了白种人男性将大豆苷分解代谢为雌马酚的情况, 结果发现有的人能将大豆苷彻底分解为雌马酚, 而有的人体内未检测到雌马酚产生. 大豆苷体内代谢差异还与人种有关[38], 对比调查韩裔美国人(Korean American, KA)和美国白人(Caucasian American, CA)体内大豆苷代谢方式. 结果发现大豆苷在KAs体内的代谢产物多是雌马酚, 而在CAs体内多为ODMA. Rafii et al[32]观察了取自4份人粪便标本中的肠道细菌对大豆异黄酮的代谢情况, 其中一份标本中检测到双氢大豆黄酮苷元; 另一份中检测到双氢大豆黄酮苷元和雌马酚; 其他两份标本中检测到ODMA和雌马酚. 说明人群中不同个体肠道菌群对同一中药成分的生物转化产物存在差异, 而正由于此差异导致了不同个体的苷类药效差异.
同时, 苷类中药体内代谢研究结果亦发现不同肠道细菌的生物转化作用不同. Wang et al[39]从人粪便标本中分离出一株G+性、厌氧杆菌Julong 732. 此株细菌能将双氢大豆黄酮苷元转化为S-雌马酚, 却不能对大豆苷苷元发挥同样作用. Tamura et al[40]从粪便标本中分离到一株与Coprobacillus catenaformis(AB030218)有93%相似性的肠道菌株TM-40. 此菌株将大豆苷及其苷元分解为双氢大豆黄酮苷元, 但不能将分解产物进一步转化为雌马酚. 由此可见, 不同菌株的生物转化底物及代谢产物均不相同, 说明不同个体药效差异是由于不同个体肠道菌群组成差异.
肠道细菌菌株生物转化作用底物的选择性是由不同细菌产生的水解酶活性决定的. 这种选择性除了与苷元结构、与苷结合的糖基种类有关外[41], 还与糖基连接到药物化学结构基本骨架上的位置有关. 由于单糖有α及β两种端基异构体, 因此形成的苷分为α-苷及β-苷. 由D型糖衍生的苷为β-苷(如β-D-葡萄糖苷), 由L型糖衍生的苷, 多为α-苷(如α-L-鼠礼糖苷). 芒果苷是知母等16种植物性药物的主要成分, 具有抗氧化、抗细菌、抗病毒、免疫调节及抗肿瘤等多方面的生理活性和药理作用[42-45]. Sanugul et al[46]从人粪便标本中分离出一细菌新种MANG, 具有将芒果苷生物转化为其苷元的能力. 此菌株分泌的酶能够裂解C-糖基, 其活性完全不同于其他裂解O-糖苷的葡糖苷酶活性.
Marotti et al[47]以黄豆(Phaseolus vulgaris L.)果实和苗中的苷类为作用底物, 观察5种人源双歧杆菌菌株的β-葡萄糖苷酶活性. 研究结果发现观察菌株均能够将山柰酚3-O-葡萄糖苷(kaempferol 3-O-glucoside)、大豆苷、染料木苷和黄豆黄苷代谢为相应的苷元. 认为在摄入豆类时, 此5株双歧杆菌可作为添加剂来提高豆类中苷类的保健作用.
Decroos et al[48]从人粪便标本中分离到一种将大豆苷有效转化为雌马酚的混合细菌培养物(a mixed microbial culture, EPC4), 此EPC4由4个菌株组成, 即Enterococcus faecium EPI1, Lactobacillus mucosae EPI2, Finegoldia magna EPI3和Veillonella sp.相关菌株EP. 将EPC4加入人类肠道微生态系统模拟装置(the human intestinal microbial ecosystem, SHIME)后, 在SHIME中共孵育大豆苷粉末和体内不能产生雌马酚者的粪便标本, 结果在SHIME中结肠末端小室检测到了雌马酚. 且未观察到加入EPC4对肠道菌群组成和活性产生明显影响, 认为在饮食中摄入EPC4是一种使体内不能产生雌马酚者产生雌马酚的新方法.
研究发现Streptococcus thermophilus, Lactobacillus, Bifidobacterium等菌株均可生物转化豆奶中的各种大豆异黄酮成分[49-51]. Tsangalis et al[52]在绝经后妇女中进行了摄入双歧杆菌发酵豆奶的初步实验, 以尿中雌马酚排出量为观察指标, 发现双歧杆菌的摄入可影响尿中雌马酚的排出量, 摄入双歧杆菌组体内雌马酚排出量比不摄入组略高.
人肠道细菌转化活性研究目前还存在着许多问题. 如何更好地模拟肠内环境, 建立良好的试验模型是十分必要, 也是迄待解决的问题. 常用体外模型包括肠液中药成分生物转化模型、粪便培养基模型以及厌氧性连续培养系统[53-55]. 前者是取肠道内容物用厌氧培养基预培养, 再与药物成分共孵育一段时间后, 取样分析; 后两者是利用新鲜粪便含有的细菌来代表肠内细菌组成. 体外模型存在温育时间长的限制. 在温育过程中, 因无肠道内生物和非生物条件的束缚, 细菌在缓冲液以及培养基中放置时间稍长, 感受态细菌丧失, 其他细菌增加, 其结果必然导致菌群组成、转化活性发生变化, 从而不能反映体内真实情况. 而悉生动物模型被称为在隔离器内饲养的整体人肠道菌群模型, 代表性好, 但技术要求高, 在一般实验室中难以实现. 另外, 当分离肠道细菌时, 由于肠道细菌数目众多, 其中约60%-80%的细菌目前尚无法培养, 存在难以得到所需要的功能菌株的缺陷. 同时人体肠道微生态系统存在定位、定性及定量的动态平衡, 具有特异性功能的肠道细菌摄入体内后由于增殖数量受到限制而很难发挥作用.
由于肠道菌群组成的个体差异导致了苷类中药个体应用的差异, 从而影响了苷类中药的药效发挥. 因此为了提高苷类中药的生物利用度, 可从肠道生理状态的肠道菌群的生物活性入手, 鉴别出具有生物转化苷类中药活性的特异性肠道细菌菌属和菌株, 将之与苷类中药同时摄入, 将有助于将苷转化为苷元, 消除苷类中药人群中应用的个体差异, 提高苷类中药的生物利用度, 进而提高苷类中药的药效.
苷类中药生物利用度低, 摄入后需经肠道细菌代谢成苷元发挥其药理作用. 人群中不同个体肠道菌群对同一苷类中药成分的生物转化作用不同, 及不同菌株的生物转化底物和代谢产物亦不相同, 是苷类中药药效个体差异的原因.
赵平, 副教授, 中国人民解放军第二军医大学微生物学教研室
Hein et al从刚处死的猪盲肠中分离猪肠道微生物菌群, 采用荧光素原位杂交法(FISH)分析分离的猪肠道菌群特征, 结果证实此猪肠道菌群体外模型适用于人类肠道菌群代谢的研究, 从而为研究苷类中药的肠道细菌生物转化拓宽了研究方法.
本文根据国内外最新资料, 介绍苷类中药肠道细菌生物转化的最新进展, 提出将具有生物转化苷类中药活性的特异性肠道细菌菌属和菌株与苷类中药同时摄入, 将有助于消除苷类中药人群中应用的个体差异.
人类肠道微生态系统模拟装置(SHIME): 是一种模拟人体肠道微生态系统、类似于人体肠道微生态系统孵化过程的5步反应器. 前2步模拟小肠的微生物生态环境, 后3步模拟大肠的微生物生态环境, 可用于分析肠道微生物多样性及活性, 获得的数据具有良好的体内外相关性.
本文阐述全面, 重点明确, 层次清晰, 具有很好的学术价值.
编辑:李军亮 电编:何基才
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