Advance in Research on Platycodonis Radix and Preliminary Analysis of Its Quality Marker Prediction
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摘要: 桔梗是桔梗科植物桔梗Platycodon grandiflorum (Jacq.) A. DC的干燥根,主要含有皂苷、黄酮、多糖、甾醇和脂肪酸等化学成分,现代研究表明其具有祛痰止咳、抗炎、抗肿瘤、降血糖、抗肥胖、免疫调节等药理作用。从桔梗化学成分、药理作用、体内过程、毒性及溶血性和质量标准等5个方面进行了系统综述,并对其质量标志物进行了探讨,以期为桔梗的进一步研究与开发提供参考。Abstract: Platycodonis Radix is the dried root of Platycodon grandiflorum (Jacq.) A. DC, which mainly contains saponins, flavonoids, polysaccharides, sterols and fatty acids. Modern studies have shown that Platycodonis Radix has pharmacological effects such as expectant and cough relieving, anti-inflammatory, anti-tumor, hypoglycemic, anti-obesity and immunoregulation.In this paper, the chemical constituents, pharmacological activities, in vivo process, toxicity, hemolysis and quality standard of Platycodonis Radix were systematically reviewed, and the quality markers of Platycodonis Radix were also discussed, in order to provide reference for further research and development of Platycodonis Radix. KEYWORDS: Platycodonis Radix; chemical composition; pharmacological activities; Q-marker
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Keywords:
- Platycodonis Radix /
- chemical composition /
- pharmacological activities /
- Q-marker
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桔梗为桔梗科植物桔梗Platycodon grandiflorum (Jacq.) A. DC的干燥根,始载于《神农本草经》,性平,味苦、辛,归肺经,具有宣肺、利咽、祛痰和排脓的功效,主治咳嗽痰多、胸闷不畅、咽痛音哑和肺痈吐脓[1]。
桔梗是多年生草本植物,在我国南北方皆有产出,主产于安徽、河南、河北和内蒙古等地区,国外如日本、朝鲜等地也有产出。随着药材需求量加大,现今的桔梗主要来源于栽培,以安徽太和、山东淄博和内蒙古赤峰产量最为丰富[2]。桔梗是一种传统药食同源的中药材,不仅具有较好的药用价值,还可作为一种食品,我国朝鲜族人民将其制成泡菜食用。
本文从桔梗的化学成分、药理作用、体内过程、毒性及溶血性和质量标准等五个方面进行了综述, 并在此基础上进一步探讨其质量标志物,为桔梗的研究和科学质量控制提供参考。
1. 化学成分
1.1 皂苷类化合物
从桔梗中分离得到的皂苷类化合物均为齐墩果烷型的五环三萜,桔梗皂苷上所连的糖基主要有D-葡萄糖、D-木糖、D-芹糖、L-阿拉伯糖、L-鼠李糖及其衍生物等,以C-3和C-28位连接形成糖苷键为主。迄今,已从桔梗中分离出皂苷类成分89种,根据结构可以分为以下8种,如图 1所示,分别为A:母核在24位连接-CH2OH;B:母核在24位连接-CH3;C:母核在24位连接-COOR,1位连接-OR;D:母核24位和2位由酯键相连;E:母核在24位连接-CH2OH,16位为羰基;F:母核在23位连接-CH3,24位连接-R,2位连接-OR,21位连接-OR,17位连接-COOH;G:母核在28位和13位由酯键相连,在24位连接-OR,12位连接-CH3;H:母核在23和24位连接-CH3,3位连接-GlcO,16位连接-OR,12位连接-OR,17位连接-COOH。见表 1。
表 1 桔梗皂苷类化合物No 化合物 分子式 类型 R1 R2 R3 R4 参考文献 1 Platycodigenin C30H48O7 A H H - - [3] 2 Platycodin A(2"-O-Acetyl platycodin D) C59H94O29 A Glc S8 - - [3] 3 Platycodin C(3"-O-Acetyl platycodin D) C59H94O29 A Glc S7 - - [3] 4 Platycodin D C57H92O28 A Glc S4 - - [4] 5 Platycodin D2 C63H102O33 A GEN S4 - - [5] 6 Platycodin D3 C63H102O33 A GEN S4 - - [4] 7 Platycodin J C57H90O29 A GlcA S4 - - [6] 8 Platycodin K C59H92O30 A GlcA S8 - - [6] 9 Platycodin L C59H92O30 A GlcA S7 - - [6] 10 2''-O-Acetyl platycodin D2 C65H104O34 A LAM S8 - - [7] 11 2''-O-Acetyl platycodin D3 C65H104O34 A GEN S8 - - [7] 12 3''-O-Acetyl platycodin D2 C65H104O34 A LAM S7 - - [8] 13 3''-O-Acetyl platycodin D3 C65H104O34 A GEN S7 - - [7] 14 Deapi-Platycodin D C52H84O24 A Glc S3 - - [4] 15 Deapi-Platycodin D2 C58H94O29 A LAM S3 - - [9] 16 Deapi-Platycodin D3 C58H94O29 A GEN S3 - - [4] 17 Deapi-3''-O-acetyl platycodin D C54H86O25 A Glc S5 - - [8] 18 Deapi-2''-O-acetyl platycodin D2 C60H96O30 A LAM S6 - - [7] 19 Platycoside A C58H94O29 A LAM S3 - - [10] 20 Platycoside B C54H86O25 A Glc S6 - - [10] 21 Platycoside C C54H86O25 A Glc S5 - - [10] 22 Platycoside E C69H112O38 A S1 S4 - - [11] 23 Platycoside F C47H76O20 A Glc S2 - - [12] 24 Platycoside G1(Deapi-platycoside E) C64H104O34 A S1 S3 - - [13] 25 Platycoside G2 C59H96O30 A GEN S2 - - [13] 26 Platycoside I C64H104O33 A S1 S3 - - [12] 27 Platycoside J C52H84O23 A Glc S3 - - [12] 28 Platycoside K C42H68O17 A LAM H - - [12] 29 Platycoside L C42H68O17 A GEN H - - [12] 30 Platycoside P C53H86O25 A LAM S2 - - [14] 31 β-Gentiotriosylplatycodigenin C48H78O22 A S1 Ara - - [7] 32 3-O-β-D-Glucopyranosyl platycodigenin C36H58O12 A Glc H - - [15] 33 3-O-β-D-Glucopyranosyl platycodigenin methyl ester C37H60O12 A Glc CH3 - - [16] 34 3-O-β-Gentiotriosyl platycodigenin methyl ester C43H70O17 A GEN CH3 - - [16] 35 3-O-β-Laminaribiosyl platycodigenin methyl ester C43H70O17 A LAM CH3 - - [16] 36 Platycoside D C69H112O37 B S1 S4 - - [11] 37 Platycoside G3(Polygalacin D3) C63H102O32 B GEN S4 - - [13] 38 Platycoside H C58H94O28 B GEN S3 - - [12] 39 Platycoside N C53H86O24 B GEN S2 - - [17] 40 Polygalacic acid C30H48O6 B H H - - [3] 41 Polygalacin D C57H92O27 B Glc S4 - - [4] 42 Polygalacin D2 C63H102O32 B LAM S4 - - [7] 43 2''-O-Acetyl-polygalacin D C59H94O28 B Glc S8 - - [4] 44 2''-O-Acetyl-polygalacin D2 C65H104O33 B LAM S8 - - [9] 45 3''-O-Acetyl-polygalacin D C59H94O28 B Glc S7 - - [4] 46 3''-O-Acetyl-polygalacin D2 C65H104O33 B LAM S7 - - [9] 47 3''-O-Acetyl-polygalacin D3 C65H104O34 B GEN S7 - - [8] 48 Deapi-polygalacin D2 C58H94O28 B LAM S3 - - [8] 49 Deapi-polygalacin D3 C58H94O28 B GEN S3 - - [7] 50 Deapi-2''-O-acetyl polygalacin D2 C60H95O30 B LAM S6 - - [8] 51 Deapi-2''-O-acetyl polygalacin D3 C60H95O30 B GEN S6 - - [8] 52 Dexyl-2''-O-acetyl-polygalacin D3 C55H87O25 B GEN S9 - - [8] 53 β-Gentiobiosyl-platycodigenin C42H68O16 B GEN Ara - - [7] 54 3-O-β-D-glucopyranosyl polygalacic acid C36H58O11 B Glc H - - [18] 55 3-O-β-D-Laminaribiosyl polygalacic acid C42H68O16 B LAM H - - [18] 56 Methyl-3-O-β-D-glucopyranosyl polygalacate C37H60O11 B Glc CH3 - - [16] 57 Methyl-3-O-β-laminaribiosyl polygalacate C43H70O16 B LAM CH3 - - [16] 58 Platycogenic acid A C30H46O8 C H H H H [3] 59 Platyconic acid A C57H90O29 C H Glc H S4 [5] 60 Platyconic acid B C59H92O30 C H Glc H S7 [6] 61 Platyconic acid C C52H82O25 C H Glc H S3 [6] 62 Platyconic acid D C54H84O26 C H Glc H S8 [6] 63 Platyconic acid E C58H92O30 C H GEN H S3 [6] 64 Platycoside O C53H84O25 C CH3 Glc H S3 [19] 65 Platyconic acid A methyl ester C58H92O29 C CH3 Glc H S4 [5] 66 Methyl Platyconate A C58H92O29 C CH3 Glc H S4 [20] 67 Methyl 2-O-methyl platyconate A C59H94O29 C CH3 Glc CH3 S4 [20] 68 Dimethyl 2-O-methyl-3-O-β-D- Glucopyranosyl platycogenate A C39H62O13 C CH3 Glc CH CH3 [16] 69 Dimethyl 3-O-β-D-glucopyranosyl Platycogenate A C38H60O13 C CH3 Glc H CH3 [16] 70 Platycoside Q C53H82O25 D GEN S2 - - [14] 71 Platycoside M-1 C36H54O12 D Glc H - - [21] 72 Platycoside M-2 C47H72O20 D Glc S2 - - [21] 73 Platycoside M-3 C52H80O24 D Glc S3 - - [21] 74 Platyconic acid A lactone C57H88O29 D Glc S4 - - [5] 75 Platyconic acid B lactone C63H98O34 D GEN S4 - - [9] 76 Deapi-platyconic acid A lactone C52H80O25 D Glc S3 - - [5] 77 Deapi-platyconic acid B lactone C58H90O30 D GEN S3 - - [9] 78 Platycogenic acid A lactone C30H44O8 D H H - - [5] 79 3-O-β-D-glucopyranosyl platycogenic acid A lactone methyl ester C37H56O12 D Glc CH3 - - [16] 80 Platycodonoids A C29H46O5 E H H - - [15] 81 Platycodonoids B C35H56O10 E Glc H - - [15] 82 16-Oxo-platycodin D C57H90O28 E Glc S4 - - [22] 83 Platycodsaponin A C42H68O16 F CH3 Glc Glc - [6] 84 Platycogenic acid B C30H46O8 F COOH H H - [3] 85 Platycogenic acid C C30H48O6 F CH3 H H - [3] 86 3-O-β-D-glucopyranosyl-2β, 12α, 16α, 23, 24-pentahydroxy-oleanane-28(13)-lactone C36H58O13 G CH2OH Glc - - [23] 87 3-O-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl-2β, 12α, 16α, 23α-tetrahydroxy-oleanane-28(13)-lactone C42H68O17 G CH3 LAM - - [23] 88 Platycodon A C42H68O16 H Glc - - - [24] 89 Platycodon B C41H66O15 H Xyl - - - [24] 注:S1=Glc6-Glc6-Glc; S2=Ara2-rha;S3=Ara2-rha4-xyl;S4=Ara2-rha4-xyl3-api;S5=Ara2-rha(3-OAc)4-xyl;S6=Ara2-rha(2-OAc)4-xyl;S7=Ara2-rha(3-OAc)4-xyl3-api;S8=Ara2-rha(2-OAc)4-xyl3-api;S9=Ara2-rha(2-OAc);Glc=β-D-glucopyranosyl;Ara=α-L-arabinopyranosyl;Rha=α-L-rhamnopyranosyl;Xyl=β-D-xylopyranosyl;Api=β-D-apiofuranosyl;GlcA= D-glucuronic acid LAM(Laminaribiose)=Glc3-Glc;GEN(gentiobiose)=Glc6-Glc。 1.2 黄酮类化合物
目前已知从桔梗的花、茎、叶和种子中共分离出9种黄酮类化合物[25-26]:飞燕草素二咖啡酰芦丁醇糖苷(1)、黄杉素(2)、(2R, 3R)-黄杉素-7-O-α-L-吡喃鼠李糖基-(1→6)-β-D-吡喃葡萄糖苷(3)、槲皮素-7-O-葡萄糖苷(4)、槲皮素-7-O-芸香糖苷(5)、木犀草素-7-O-葡萄糖苷(6)、芹菜素-7-O-葡萄糖苷(7)、木犀草素(8)和芹菜素(9)。李凌军等[27]从桔梗根中分离得到蜜桔素。见图 2。
1.3 酚类化合物
桔梗根部和地上部分均检测到酚类成分的存在,目前已发现的酚类化合物有14种。Lee等[28]从桔梗根部中检测出棕榈酸松柏醇酯、油酸松柏醇酯2种酚类化合物。Mazol等[29]从桔梗地上部分检测出咖啡酸、绿原酸、阿魏酸、异阿魏酸、间香豆酸、对香豆酸、3, 4-二甲氧基肉桂酸、间羟基苯甲酸、对羟基苯甲酸、2-羟基-4-甲氧基苯甲酸、2, 3-二羟基苯甲酸和高香草酸共12种酚类化合物。
1.4 多糖类化合物
桔梗根中多糖是大量果糖聚成,主要为桔梗聚糖和菊糖型果聚糖,其中已经鉴定出结构的桔梗聚糖是GF2~GF9[30]。
1.5 其他成分
桔梗根中含有α-菠菜甾醇和其葡萄糖苷、Δ7-豆甾醇和白桦脂醇等甾醇类化合物。桔梗根中有16种以上的氨基酸,包括了8种必需氨基酸,占总氨基酸的6.44%。桔梗中分离出的脂肪酸共34种,包括了亚油酸、棕榈油酸和亚麻酸等15种不饱和脂肪酸,棕榈酸、硬脂酸和花生酸等19种饱和脂肪酸[31]。Chen等[32]从桔梗根中分离出Platetyolin A、Platetyolin B和Lobetyolin三种聚乙炔类化合物。
2. 药理作用
2.1 镇咳祛痰作用
Shin等[33]发现在体内和体外实验中桔梗中的Platycodin D和Platycodin D3增加了气道粘蛋白的释放,改善了气道呼吸功能。Ryu等[34]通过体内体外实验研究发现桔梗根水提液可以刺激气道管腔黏液分泌,诱发咳嗽反射从而促进痰液排出。
2.2 抗炎作用
桔梗皂苷D (Platycodin D)是桔梗中一种三萜皂苷类化合物,Gao等[35]发现桔梗皂苷D通过激活Nrf2和抑制NF-κB信号通路对减轻吸烟导致的肺部炎症。Fu等[36]研究发现桔梗皂苷D可以通过抑制TNF-α、IL-6和IL-1β的产生,激活LXRα-ABCA1信号通路治疗LPS诱导的神经胶质细胞炎症。
2.3 抗肿瘤作用
桔梗的抗肿瘤作用在国内外有较多的研究,桔梗中的皂苷类成分因其抗肿瘤活性引起了广泛关注。Zhang等[37]研究发现桔梗皂苷D可以增加口腔细胞鳞状细胞癌细胞中IκBκ蛋白的表达,降低了磷酸化NF-κBp65、MMP-9和MMP-2表达,抑制了NF-κB信号通路,从而对癌细胞的生长进行抑制。Li等[38]将顺铂和桔梗联合给以A549细胞,影响了PI3K/Akt信号通路,促进了细胞的凋亡,表明桔梗对顺铂有增强效用的作用。
2.4 抗肥胖作用
Hwang等[39]探究了桔梗对高脂饮食诱发的肥胖小鼠的减肥机制,桔梗提取物降低血浆中甘油三酯、总胆固醇、瘦素和低密度脂蛋白胆固醇的水平,增加了高密度脂蛋白胆固醇和脂联素的水平,抑制脂肪基因如脂肪酸合成酶和脂蛋白脂酶等的表达,增强脂肪分解基因如解偶联蛋白2等的表达,促进甘油三酯的代谢和排泄来帮助减肥。另有研究发现桔梗皂苷D可以降低脂肪组织中过氧化物酶体增殖物激活受体γ2(PPARγ2)和CCAAT/增强子结合蛋白α(C/EBPα)的表达,增加AMP激活性蛋白激酶α(AMPKα)表达,从而降低了脂肪的积累达到抗肥胖的作用[40]。
2.5 保肝作用
Khanal等[41]发现桔梗总皂苷可以通过抑制酒精诱导的CYP2E1蛋白的表达升高,AMPKα和乙酰辅酶A羧化酶的磷酸化的恢复来抑制了肝中甘油三酯的积累来治疗酒精性脂肪肝。Ke等[42]发现桔梗通过调节乙酰辅酶A羧化酶的磷酸化、脂肪酸合成酶的表达以及PI3K/Akt/GSK3β通路来改善高脂饮食诱导的非酒精性脂肪肝。Liu等[43]发现桔梗皂苷D通过对JNK/c-Jun通路的调节,诱导肝星状细胞的自噬与凋亡来减轻肝纤维化。
2.6 抗氧化作用
Sheng等[44]对桔梗中分离得到的硒多糖进行研究,通过对过氧化氢诱导的大鼠嗜铬细胞瘤细胞使用不同剂量的硒多糖预处理,发现硒多糖预处理可以抑制细胞活力的降低,降低细胞凋亡率,提高了超氧化物歧化酶的活性,降低了丙二醛的水平,表明硒多糖是一种潜在的抗氧化剂。Shi等[45]使用桔梗皂苷D在H2O2诱导的早衰细胞上,发现桔梗皂苷D可以改善线粒体的内源性氧化损伤,有抗氧化和抗衰老的作用。
2.7 增强免疫力作用
从桔梗中提取的多糖类成分具有增强免疫力的作用,Pang等[46]对桔梗中的菊糖型果聚糖进行研究,发现其对肠上皮细胞有较好的免疫调节作用并且对抗炎因子的表达有刺激作用。Noh等[47]发现桔梗水提液能够增强细胞活性,能对环磷酰胺治疗的大鼠体内的白细胞、中性粒细胞减少的恢复,提高血清中炎症细胞因子(TNF-α、IFN-γ、IL-2和IL-12)和免疫球蛋白(IgG和IgA)的水平,从而减轻了环磷酰胺导致的免疫抑制的损伤。
2.8 保护心血管作用
Luo等[48]对桔梗皂苷D在血小板功能以及血栓形成中的作用进行了研究,发现桔梗皂苷D可以抑制血小板聚集和组织血栓的形成。Choi等[49]发现桔梗皂苷D通过抑制LXR-IDOL途径诱导低密度脂蛋白受体(LDLR)表达从而提高LDL-C的摄取,表明桔梗皂苷D可以作为动脉粥样硬化心血管疾病的潜在选择。
2.9 其他作用
Zhang等[50]研究发现桔梗总皂苷通过抑制NF-κB的活性和调节PI3K/Akt信号通路来保护顺铂造成的肾损伤。Kim等[51]发现桔梗根提取物可以激活EPK1/2信号通路来增加突触形成,进而增强小鼠认知功能。Kim等[52]发现桔梗总皂苷可以通过改善骨骼肌蛋白质合成和线粒体功能来增强运动功能。
3. 体内过程研究
本课题组比较了灌胃桔梗皂苷D和桔梗提取物后桔梗皂苷D在大鼠体内药代动力学的差异,发现在灌胃20 mg/kg的桔梗皂苷D和等量桔梗皂苷D的桔梗提取物后,分别在30 min和75 min达到最大血药浓度,各为44.5 ng/mL和17.94 ng/mL,药物浓度-时间曲线下面积(AUC)各为(73±24.17) h·ng/mL和(96.06±48.51)h·ng/mL,说明桔梗提取物中桔梗皂苷D的吸收入血程度更高[53]。对于复方中桔梗皂苷D的体内过程,课题组也有研究,灌胃桔梗甘草药对发现甘草提高了桔梗中桔梗皂苷D的最大血药浓度和药物浓度-时间曲线下面积(AUC),同时延长了半衰期(T1/2)[54]。
Kwon等[55]通过口服和静脉给药桔梗皂苷D(30 mg/kg和0.5 mg/kg),口服桔梗皂苷D时,最大血药浓度(788±491)ng/mL,血药浓度达峰时间(Tmax)为(2.13±1.3)h,药物浓度-时间曲线下面积(AUC)为(5 042±2 580)h·ng/mL,半衰期(T1/2)为(5.42±1.9)h,生物利用度为1.89%;静脉注射时的半衰期(T1/2)为(2.14±0.18)h,药物浓度-时间曲线下面积(AUC)为(3 843±538)h·ng/mL。
4. 毒性及溶血性研究
Cha等[56]通过对SD大鼠分别给予高中低3个剂量组[3 000、1 000、500 mg/(kg·d)]13周桔梗水提物,发现肝脏小叶中心型肝细胞肥大的发生率增加,甲状腺弥漫性滤泡细胞肥大,但这些被认为是适应性变化,同时3个剂量组都未出现靶器官,表明口服桔梗水提物3 000 mg/(kg·d)剂量以下没有毒性。Lee等[57]研究了小鼠口服桔梗皂苷D的毒性,以2 000、1 000、500、250、125 mg/kg进行灌胃未发现有死亡,且组织病理学也未发现有异常变化,表明2 000 mg/kg以下的口服剂量对小鼠没有毒性。
Sun等[58]对桔梗中桔梗皂苷D(Platycodin D:PD)、桔梗皂苷D2(Platycodin D2:PD2)、桔梗皂苷D3(Platycodin D3:PD3)、桔梗皂苷E(Platycodin E:PE)、去芹糖桔梗皂苷E(Deapi-Platycodin E:DPE)、远志皂苷D2(Polygalacin D2:PGD)和platycoside A(PA)的溶血性做了研究,结果显示溶血活性顺序是PGD≈PD> PD2>PA>PD3>PE> DPE,其溶血性随着C-3位的糖数目的增加和C-28位的糖数目减少而变化。
5. 质量标准研究
2020年版《中国药典》对桔梗的性状、鉴别、检查、浸出物和含量测定做出了规定,并通过HPLC-ELSD检测桔梗中桔梗皂苷D的含量来评判桔梗质量,即按干燥品计算,含桔梗皂苷D的含量不得少于0.10%。
谭玲玲等[59]对17个产地的桔梗中的总皂苷和桔梗皂苷D分别使用称重法和HPLC-UV进行测定,发现桔梗总皂苷的含量和桔梗皂苷D的含量没有必然联系。蒋龄周等[60]使用HPLC-ELSD,通过一测多评法对桔梗中桔梗皂苷D、桔梗皂苷D3和桔梗皂苷E的含量进行测定。喻格等[61]使用气相色谱-质谱联用法测定了桔梗中的挥发油成分。司雨柔等[62]使用傅里叶变换红外光谱和显微红外光谱对不同产地的桔梗中化学成分的红外光谱图库进行分析,发现同省不同产地没有较大的区别,不同省的桔梗中物质成分和含量有一定的差异。陈宝等[63]使用UPLC技术同时测定不同产地桔梗中的13种核苷类物质,发现不同产地中的核苷差异较大。许传莲等[64]对不同采收期的桔梗中桔梗皂苷D含量进行测定,发现桔梗皂苷D含量在春季4月时较低,5月开始上升,9月和10月的桔梗中桔梗皂苷D含量达到最高,进入秋冬季11月后,含量开始下降。宋健等[65]探究了不同生长年限和桔梗药材的质量关系,发现一年生药材质地较轻且各主要成分含量较低,三年生药材和两年生药材一样质地粗重,但多糖成分和桔梗皂苷D的含量较多,总皂苷含量比两年生药材的含量有所降低。黄力等[66]使用反相高效液相色谱法探究不同干燥方法对桔梗药材中桔梗皂苷D的含量的影响,分别对新鲜药材进行晒干、60 ℃烘干、80 ℃烘干和微波干燥处理,结果显示桔梗皂苷D的含量由高到低为80 ℃烘干>60 ℃烘干>微波干燥>晒干。付志文等[67]则是发现烘干处理和晒干处理对于桔梗总皂苷的含量影响不大。本课题组[68]对10省58批药材进行了性状、浸出物、桔梗皂苷D含量及指纹图谱的比较,发现不同产地的药材性状有一定的差异,浸出物、桔梗皂苷D含量差异较大,所含成分大致相同,但在含量方面有较大差异;在这58批药材中浸出物含量最高的为吉林省,桔梗皂苷D含量最高的为四川省。
6. 对桔梗质量标志物研究的分析与思考
刘昌孝院士在2016年提出中药质量标志物(Q-marker)的概念,明确中药质量标志物的基本条件[69]是:①存在于中药材和中药产品中固有的次生代谢物,或加工制备过程中形成的化学物质;②来源某药材(饮片)特有的而不是来源于其他药材的化学物质;③有明确的化学结构和生物活性;④可以进行定性鉴别和定量测定的物质;⑤按中医配伍组成的方剂“君”药首选原则,兼顾“臣”“佐”“使”药的代表性物质。
桔梗中的成分复杂,主要有三萜皂苷类、黄酮类和多糖类等成分,但桔梗的药用部位是根部,根部含有成分为三萜皂苷类、多糖类、酚类、脂肪酸、甾醇、氨基酸和聚乙炔类和黄酮类化合物,所以将以上几类成分列入桔梗质量标志物的选择中,而化学成分作为质量标志物需有定性和定量测定的方法,皂苷类成分一般是测定其总皂苷或特征性皂苷成分如桔梗皂苷D作为质量评价指标,而多糖类成分因其结构复杂,定性较为困难,一般测定其中总多糖成分含量作为质量评价指标,对于桔梗中的其他成分则需要发展新的制备方法和检测技术。
药性和药效反映了中药的有效性,将药性和药效纳入质量评价中可以更好体现中药质量评价的完整性。桔梗苦、辛,平,归肺经。现代研究表明苦味多源于生物碱类成分,辛多源于挥发油、皂苷及生物碱类成分,因此将皂苷类成分作为质量标志物的参考。桔梗在现代药理学研究中发现具有祛痰镇咳、抗炎、抗肥胖等作用,主要发挥效用物质是皂苷类成分如桔梗皂苷D和多糖类成分如桔梗菊糖型果聚糖,可将桔梗皂苷D和菊糖型果聚糖作为质量标志物的选择参考。同时,药物发挥效用需要进入血液中,达到有效浓度,桔梗中具有的有效成分如皂苷类和多糖类成分,胃肠吸收差,通常在肠道菌的作用下生成次级代谢产物发挥效用,对于桔梗中入血成分尚未明确,因此这一方面的内容有待进一步研究。
处方配伍是指质量评价需要结合临床应用方面,针对处方配伍环境和临床应用时起效成分来确定作为质量评价的成分。桔梗一般与其他药进行配伍使用,如桔梗在桔梗汤中的使用,桔梗汤最早记载于《伤寒论》中,具有宣肺利咽、清热解毒的功效,现代研究表明,桔梗汤所具有的宣肺止咳、利咽解毒和祛痰排脓功效的活性成分为桔梗中皂苷类成分[70],所以将桔梗中皂苷类成分作为该处方的质量评价成分。
现行的2020年版《中国药典》对桔梗质量评价方面仍有待进一步完善,本文提出结合中药质量标志物的研究思路对桔梗质量评价进行拓展与延伸,为今后开展桔梗质量研究提供些许参考。
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表 1 桔梗皂苷类化合物
No 化合物 分子式 类型 R1 R2 R3 R4 参考文献 1 Platycodigenin C30H48O7 A H H - - [3] 2 Platycodin A(2"-O-Acetyl platycodin D) C59H94O29 A Glc S8 - - [3] 3 Platycodin C(3"-O-Acetyl platycodin D) C59H94O29 A Glc S7 - - [3] 4 Platycodin D C57H92O28 A Glc S4 - - [4] 5 Platycodin D2 C63H102O33 A GEN S4 - - [5] 6 Platycodin D3 C63H102O33 A GEN S4 - - [4] 7 Platycodin J C57H90O29 A GlcA S4 - - [6] 8 Platycodin K C59H92O30 A GlcA S8 - - [6] 9 Platycodin L C59H92O30 A GlcA S7 - - [6] 10 2''-O-Acetyl platycodin D2 C65H104O34 A LAM S8 - - [7] 11 2''-O-Acetyl platycodin D3 C65H104O34 A GEN S8 - - [7] 12 3''-O-Acetyl platycodin D2 C65H104O34 A LAM S7 - - [8] 13 3''-O-Acetyl platycodin D3 C65H104O34 A GEN S7 - - [7] 14 Deapi-Platycodin D C52H84O24 A Glc S3 - - [4] 15 Deapi-Platycodin D2 C58H94O29 A LAM S3 - - [9] 16 Deapi-Platycodin D3 C58H94O29 A GEN S3 - - [4] 17 Deapi-3''-O-acetyl platycodin D C54H86O25 A Glc S5 - - [8] 18 Deapi-2''-O-acetyl platycodin D2 C60H96O30 A LAM S6 - - [7] 19 Platycoside A C58H94O29 A LAM S3 - - [10] 20 Platycoside B C54H86O25 A Glc S6 - - [10] 21 Platycoside C C54H86O25 A Glc S5 - - [10] 22 Platycoside E C69H112O38 A S1 S4 - - [11] 23 Platycoside F C47H76O20 A Glc S2 - - [12] 24 Platycoside G1(Deapi-platycoside E) C64H104O34 A S1 S3 - - [13] 25 Platycoside G2 C59H96O30 A GEN S2 - - [13] 26 Platycoside I C64H104O33 A S1 S3 - - [12] 27 Platycoside J C52H84O23 A Glc S3 - - [12] 28 Platycoside K C42H68O17 A LAM H - - [12] 29 Platycoside L C42H68O17 A GEN H - - [12] 30 Platycoside P C53H86O25 A LAM S2 - - [14] 31 β-Gentiotriosylplatycodigenin C48H78O22 A S1 Ara - - [7] 32 3-O-β-D-Glucopyranosyl platycodigenin C36H58O12 A Glc H - - [15] 33 3-O-β-D-Glucopyranosyl platycodigenin methyl ester C37H60O12 A Glc CH3 - - [16] 34 3-O-β-Gentiotriosyl platycodigenin methyl ester C43H70O17 A GEN CH3 - - [16] 35 3-O-β-Laminaribiosyl platycodigenin methyl ester C43H70O17 A LAM CH3 - - [16] 36 Platycoside D C69H112O37 B S1 S4 - - [11] 37 Platycoside G3(Polygalacin D3) C63H102O32 B GEN S4 - - [13] 38 Platycoside H C58H94O28 B GEN S3 - - [12] 39 Platycoside N C53H86O24 B GEN S2 - - [17] 40 Polygalacic acid C30H48O6 B H H - - [3] 41 Polygalacin D C57H92O27 B Glc S4 - - [4] 42 Polygalacin D2 C63H102O32 B LAM S4 - - [7] 43 2''-O-Acetyl-polygalacin D C59H94O28 B Glc S8 - - [4] 44 2''-O-Acetyl-polygalacin D2 C65H104O33 B LAM S8 - - [9] 45 3''-O-Acetyl-polygalacin D C59H94O28 B Glc S7 - - [4] 46 3''-O-Acetyl-polygalacin D2 C65H104O33 B LAM S7 - - [9] 47 3''-O-Acetyl-polygalacin D3 C65H104O34 B GEN S7 - - [8] 48 Deapi-polygalacin D2 C58H94O28 B LAM S3 - - [8] 49 Deapi-polygalacin D3 C58H94O28 B GEN S3 - - [7] 50 Deapi-2''-O-acetyl polygalacin D2 C60H95O30 B LAM S6 - - [8] 51 Deapi-2''-O-acetyl polygalacin D3 C60H95O30 B GEN S6 - - [8] 52 Dexyl-2''-O-acetyl-polygalacin D3 C55H87O25 B GEN S9 - - [8] 53 β-Gentiobiosyl-platycodigenin C42H68O16 B GEN Ara - - [7] 54 3-O-β-D-glucopyranosyl polygalacic acid C36H58O11 B Glc H - - [18] 55 3-O-β-D-Laminaribiosyl polygalacic acid C42H68O16 B LAM H - - [18] 56 Methyl-3-O-β-D-glucopyranosyl polygalacate C37H60O11 B Glc CH3 - - [16] 57 Methyl-3-O-β-laminaribiosyl polygalacate C43H70O16 B LAM CH3 - - [16] 58 Platycogenic acid A C30H46O8 C H H H H [3] 59 Platyconic acid A C57H90O29 C H Glc H S4 [5] 60 Platyconic acid B C59H92O30 C H Glc H S7 [6] 61 Platyconic acid C C52H82O25 C H Glc H S3 [6] 62 Platyconic acid D C54H84O26 C H Glc H S8 [6] 63 Platyconic acid E C58H92O30 C H GEN H S3 [6] 64 Platycoside O C53H84O25 C CH3 Glc H S3 [19] 65 Platyconic acid A methyl ester C58H92O29 C CH3 Glc H S4 [5] 66 Methyl Platyconate A C58H92O29 C CH3 Glc H S4 [20] 67 Methyl 2-O-methyl platyconate A C59H94O29 C CH3 Glc CH3 S4 [20] 68 Dimethyl 2-O-methyl-3-O-β-D- Glucopyranosyl platycogenate A C39H62O13 C CH3 Glc CH CH3 [16] 69 Dimethyl 3-O-β-D-glucopyranosyl Platycogenate A C38H60O13 C CH3 Glc H CH3 [16] 70 Platycoside Q C53H82O25 D GEN S2 - - [14] 71 Platycoside M-1 C36H54O12 D Glc H - - [21] 72 Platycoside M-2 C47H72O20 D Glc S2 - - [21] 73 Platycoside M-3 C52H80O24 D Glc S3 - - [21] 74 Platyconic acid A lactone C57H88O29 D Glc S4 - - [5] 75 Platyconic acid B lactone C63H98O34 D GEN S4 - - [9] 76 Deapi-platyconic acid A lactone C52H80O25 D Glc S3 - - [5] 77 Deapi-platyconic acid B lactone C58H90O30 D GEN S3 - - [9] 78 Platycogenic acid A lactone C30H44O8 D H H - - [5] 79 3-O-β-D-glucopyranosyl platycogenic acid A lactone methyl ester C37H56O12 D Glc CH3 - - [16] 80 Platycodonoids A C29H46O5 E H H - - [15] 81 Platycodonoids B C35H56O10 E Glc H - - [15] 82 16-Oxo-platycodin D C57H90O28 E Glc S4 - - [22] 83 Platycodsaponin A C42H68O16 F CH3 Glc Glc - [6] 84 Platycogenic acid B C30H46O8 F COOH H H - [3] 85 Platycogenic acid C C30H48O6 F CH3 H H - [3] 86 3-O-β-D-glucopyranosyl-2β, 12α, 16α, 23, 24-pentahydroxy-oleanane-28(13)-lactone C36H58O13 G CH2OH Glc - - [23] 87 3-O-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl-2β, 12α, 16α, 23α-tetrahydroxy-oleanane-28(13)-lactone C42H68O17 G CH3 LAM - - [23] 88 Platycodon A C42H68O16 H Glc - - - [24] 89 Platycodon B C41H66O15 H Xyl - - - [24] 注:S1=Glc6-Glc6-Glc; S2=Ara2-rha;S3=Ara2-rha4-xyl;S4=Ara2-rha4-xyl3-api;S5=Ara2-rha(3-OAc)4-xyl;S6=Ara2-rha(2-OAc)4-xyl;S7=Ara2-rha(3-OAc)4-xyl3-api;S8=Ara2-rha(2-OAc)4-xyl3-api;S9=Ara2-rha(2-OAc);Glc=β-D-glucopyranosyl;Ara=α-L-arabinopyranosyl;Rha=α-L-rhamnopyranosyl;Xyl=β-D-xylopyranosyl;Api=β-D-apiofuranosyl;GlcA= D-glucuronic acid LAM(Laminaribiose)=Glc3-Glc;GEN(gentiobiose)=Glc6-Glc。 -
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