甘草酸苷作用機制的研究進展

王 穎，韓秀萍

0 引言

甘草酸苷(Glycyrrhizin，GL)又稱甘草酸、甘草皂苷或甘草甜素，是甘草的主要活性成分，具有保護肝細(xì)胞、抗炎、抗病毒、免疫調(diào)節(jié)以及抗腫瘤等多種藥理作用和生物學(xué)功能。甘草酸苷的療效雖已在臨床應(yīng)用中得到廣泛認(rèn)可，但其作用機制仍不完全清楚，現(xiàn)就近年來甘草酸苷作用機制的研究進展做一簡要綜述。

1 甘草酸苷的結(jié)構(gòu)

甘草酸苷是從甘草根部提取的三萜苷(圖1)[1]，占甘草總提取物的3.63%～13.06%，是甘草的主要活性成分。甘草酸苷可被腸內(nèi) β-D-葡萄糖醛酸糖苷酶水解為一分子18β-甘草次酸和兩分子葡萄糖醛酸[2-3]。18β-甘草次酸具有類皮質(zhì)醇樣結(jié)構(gòu)[4]，可通過抑制11β-羥基固醇脫氫酶的活性模擬皮質(zhì)醇的作用[5-6]。

圖1 甘草酸苷的化學(xué)結(jié)構(gòu)

2 甘草酸苷的作用機制

2.1 抗炎作用 目前已知的甘草酸苷抗炎作用機制主要有2種，一種為通過抑制花生四烯酸的代謝水平，抑制細(xì)胞色素C(CytC)的釋放，從而抑制磷脂酶A2(PLA2)的活性，抑制補體激活；一種為非特異性的抗炎及保護細(xì)胞膜的作用，抑制熱休克蛋白90(HSP-90)的表達，從而降低糖皮質(zhì)激素受體與配體的親和力[7-10]。

2.1.1 肝細(xì)胞保護作用 肝臟是機體最大的代謝器官和重要的免疫器官，其解毒和吞噬功能對機體有重要保護作用。各種致病因子作用于肝組織后，可直接導(dǎo)致肝細(xì)胞不同程度的損傷，還可通過自分泌和旁分泌作用引起細(xì)胞因子網(wǎng)絡(luò)的激活，引起肝細(xì)胞的損傷、肝纖維化等，晚期則發(fā)展為肝硬化和肝癌。甘草酸苷被廣泛應(yīng)用于治療肝細(xì)胞損傷和慢性肝炎[11-13]。

肝臟發(fā)生炎癥時，會伴有環(huán)氧化酶-2(COX-2)、腫瘤壞死因子-α(TNF-α)、白介素-6(IL-6)以及誘生型一氧化氮合酶(iNOS)水平的升高，進而引起肝細(xì)胞炎癥和凋亡。甘草酸苷可降低這些炎癥因子的表達，抑制核因子-κB(NF-κB)的活性，減輕TNF-α-MAPK-NF-κB 途徑所致的肝細(xì)胞損傷和凋亡[14-16]。另有研究發(fā)現(xiàn)，長時間腸外營養(yǎng)可引起嚴(yán)重的肝臟疾病，預(yù)防性的甘草酸苷治療，可下調(diào)內(nèi)質(zhì)網(wǎng)應(yīng)激因子，如c-Jun氨基末端激酶(JNK)、p38絲裂原活化蛋白激酶(p38 MAPK) 和C/EBP環(huán)磷酸腺苷反應(yīng)元件結(jié)合轉(zhuǎn)錄因子同源蛋白(CHOP)的水平，減輕肝損傷[17]。動物實驗發(fā)現(xiàn)，在代謝綜合征中存在肝功能異常，包括丙氨酸氨基轉(zhuǎn)移酶(ALT)、天冬氨酸氨基轉(zhuǎn)移酶(AST)和谷氨酰轉(zhuǎn)肽酶(GGT)的水平升高，給予甘草酸苷后，這些指標(biāo)可恢復(fù)正常。對肝臟組織檢查發(fā)現(xiàn)，用藥后肝細(xì)胞線粒體中活性氧簇(ROS)減少，說明甘草酸苷可以改善線粒體的氧化性應(yīng)激[18]。這種保護機制同樣發(fā)生于丙型肝炎病毒感染的肝臟組織[19]。

2.1.2 其他抗炎作用 近年來，甘草酸苷作為高遷移率族蛋白-1(HMGB1)的天然抑制劑，其抗炎作用越來越受到關(guān)注。HMGB1是核內(nèi)高度保守的非組蛋白染色體蛋白，主要穩(wěn)定核小體的結(jié)構(gòu)并調(diào)節(jié)基因轉(zhuǎn)錄。HMGBl可以主動或被動從細(xì)胞中釋放，作為細(xì)胞因子和內(nèi)源性信號分子與多種細(xì)胞表面不同的受體如高級糖化終產(chǎn)物(RAGE)[20]，Toll樣受體2(TLR2)[21]、TLR4[22]結(jié)合，活化下游信號，如p38MAPK[23-24]、pJNK[25]和NF-κB，進而上調(diào)半胱天冬酶-3(Caspase-3)[26-27]、TNF-α、IL-1、IL-6的水平，引起炎癥反應(yīng)，加劇細(xì)胞損傷和凋亡。甘草酸苷可直接與HMGBl結(jié)合，抑制其細(xì)胞因子的活性[28]，在感染、燒傷、組織器官缺血性損傷、胰腺炎和潰瘍性結(jié)腸炎等炎性疾病中發(fā)揮治療作用。

另有研究發(fā)現(xiàn)，甘草酸苷可以降低細(xì)胞膜脂質(zhì)筏膽固醇含量，并活化ATP結(jié)合盒轉(zhuǎn)運體A-1(ABCA1)降低細(xì)胞膜脂質(zhì)筏的膽固醇外流，從而干擾TLR4向脂質(zhì)筏轉(zhuǎn)移，最終減少NF-κB和干擾素調(diào)節(jié)因子-3(IRF3)表達，下調(diào)炎性因子的水平，減輕炎癥反應(yīng)[29-30]。甘草酸苷還可以使單核細(xì)胞趨化蛋白-1(MCP-1)、巨噬細(xì)胞炎性蛋白-2(MIP-2)和中性粒細(xì)胞趨化因子-2(CINC-2)表達下降，減輕炎性細(xì)胞浸潤，改善預(yù)后[31-32]。

2.2 抗病毒作用 早在1979年，Pompei等[33]發(fā)現(xiàn)甘草酸有抗病毒活性，能抑制很多不同的DNA、RNA病毒的生長，并且不影響正常細(xì)胞的活性，還可以不可逆鈍化單純性皰疹病毒顆粒。另有研究通過免疫熒光和電子顯微鏡觀察發(fā)現(xiàn)，甘草酸苷作用于感染丙型肝炎病毒(HCV)的Huh7細(xì)胞后，細(xì)胞外病毒量下降而細(xì)胞內(nèi)的病毒量上升(HCV核心抗原和電子致密顆粒在內(nèi)質(zhì)網(wǎng)聚集)，說明甘草酸苷雖然不能阻斷HCV的入侵，但是可以抑制受感染的細(xì)胞釋放病毒顆粒[34]，并且在一定程度上可以抑制HCV的復(fù)制[35]。甘草酸苷雖然沒有清除病毒的作用，但是可以通過阻斷NF-κB抑制劑IκBκ的降解，下調(diào)炎性因子TNF-α、IL-1β和IL-6的水平，明顯改善柯薩奇病毒B3(CVB3)所致的病毒性心肌炎[36]，還可通過減少趨化相關(guān)因子CXCL10、CCL5[37]、CXCL2和CCL2的表達，減輕炎癥反應(yīng)和細(xì)胞凋亡[38-39]。

2.3 免疫調(diào)節(jié)作用 甘草酸苷具有非特異性免疫調(diào)節(jié)作用，可以通過對T細(xì)胞亞群的調(diào)節(jié)，促進胸腺外T淋巴細(xì)胞分化[40]，活化NK細(xì)胞[41]，誘導(dǎo)干擾素-γ(IFN-γ)及調(diào)節(jié)細(xì)胞因子水平等發(fā)揮作用。

甘草酸苷可以劑量依賴性地下調(diào)過敏性鼻炎小鼠模型IgE、IL-4、IL-5、IL-6、NO、TNF-α和P物質(zhì)的水平，上調(diào)IL-2、IL-12的分泌，增強乙酰膽堿酯酶(AchE)的活性，改善過敏反應(yīng)[42-43]。Bordbar等[44]和Hua等[45]研究了甘草酸苷對小鼠不同來源樹突狀細(xì)胞成熟及功能的影響，發(fā)現(xiàn)甘草酸苷作用后，樹突狀細(xì)胞表達CD40、CD86和MHC-Ⅱ增加，分泌IL-10和IL-12增多，分泌TNF-α減少，說明甘草酸苷對樹突狀細(xì)胞有正向的促成熟作用。這種樹突狀細(xì)胞與同源的T細(xì)胞共培養(yǎng)后，T細(xì)胞分泌IFN-γ、IL-10水平增加，而分泌IL-4的水平下降，說明甘草酸苷可以增強1型輔助性T細(xì)胞(Th1)為主的免疫反應(yīng)。在刀豆球蛋白A(Con.A)誘導(dǎo)的肝纖維化小鼠模型中，甘草酸苷通過調(diào)節(jié)Th1/Th2和調(diào)節(jié)性T細(xì)胞(Treg)/Th17的平衡，使免疫反應(yīng)向Th1及 Treg細(xì)胞偏斜，顯著上調(diào)IFN-γ和IL-10的水平。進一步的研究發(fā)現(xiàn)，這種作用可能是通過抑制JNK、細(xì)胞外調(diào)節(jié)蛋白激酶(ERK)和磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/AKT)的磷酸化實現(xiàn)的[46]。

2.4 抗腫瘤作用 甘草酸苷抗炎、抗氧化應(yīng)激及免疫調(diào)節(jié)等作用，使其可以用于預(yù)防和治療各種慢性炎癥所誘發(fā)的癌變。1項10年的甘草酸苷治療丙型肝炎的臨床研究顯示，甘草酸苷不僅可以改善患者肝功能，還能夠降低肝癌的發(fā)生率。進一步研究顯示，甘草酸苷可上調(diào)抑癌基因jun-B的表達，減輕慢性肝損傷[47]，促進肝癌細(xì)胞線粒體膜去極化，上調(diào)p53、CytC、B淋巴細(xì)胞瘤-2基因(Bcl-2)相關(guān)X蛋白(Bax)的表達，促進肝癌細(xì)胞凋亡[48-49]。肺腺癌細(xì)胞系A(chǔ)549和NCI-H23高表達血栓素合酶，甘草酸苷可抑制其表達和活性，從而抑制肺腺癌細(xì)胞的生長[50]。動物實驗證實，甘草酸苷通過下調(diào)由幽門螺桿菌及高鹽飲食導(dǎo)致的COX-2、iNOS、血管內(nèi)皮生長因子(VEGF)和IL-8水平升高，減輕慢性萎縮性胃炎癥狀，降低胃癌的發(fā)生率[51]。甘草次酸可增加細(xì)胞間質(zhì)中酪氨酸mRNA的水平，通過激活轉(zhuǎn)錄機制誘導(dǎo)黑色素細(xì)胞B16中黑色素生成，加速腫瘤細(xì)胞老化，起到抗黑色素瘤作用[52]。另有研究顯示，甘草酸苷可使人宮頸癌HeLa細(xì)胞核中對硫氧還蛋白(Trx)表達下降，降低腫瘤細(xì)胞的耐藥性[53]。

癌細(xì)胞在抗癌藥物的作用下，在發(fā)生壞死的同時釋放HMGB1。HMGB1作為前炎癥因子，可以促進血管內(nèi)皮細(xì)胞增生和癌細(xì)胞遷移，上調(diào)TNF-α水平，造成對正常組織和細(xì)胞的損傷，甘草酸苷與HMGB1特異性地結(jié)合，抑制其細(xì)胞因子活性，可改善由抗癌藥物引起的炎癥反應(yīng)[54]。

2.5 不良反應(yīng) 眾所周知，假性醛固酮增多癥，主要表現(xiàn)為鈉潴留、低鉀血癥和高血壓等，是甘草酸苷的主要不良反應(yīng)。Stewart等[55]研究表明，此現(xiàn)象是由18β-甘草次酸引起的，后者可抑制11β-羥基固醇脫氫酶在腎臟的代謝。11β-羥基固醇脫氫酶有2種亞型，腎型11β-脫氫酶和肝型11β-氧還原酶。腎型11β-脫氫酶可將皮質(zhì)醇轉(zhuǎn)化為腎上腺激素，肝型11β-氧還原酶則催化相反的反應(yīng)。18β-甘草次酸抑制腎型11β-脫氫酶的代謝，導(dǎo)致腎臟皮質(zhì)醇水平增加。又由于皮質(zhì)醇和醛固酮與鹽皮質(zhì)激素受體有相同的親和力，必然導(dǎo)致高鹽皮質(zhì)激素效應(yīng)，進而抑制腎素-血管緊張素-醛固酮系統(tǒng)(RAAS)，引起腎素血管緊張素Ⅰ和醛固酮水平下降、鈉潴留及尿鉀增多。

然而，一項甘草酸苷應(yīng)用于對干擾素聯(lián)合利巴韋林治療無效的丙型肝炎患者的有效性及安全性的Ⅲ期臨床研究顯示，經(jīng)靜脈給藥200 mg/d，共10周后，患者ALT明顯下降，肝細(xì)胞壞死及肝臟纖維化明顯減輕，同時，有5.5%的患者出現(xiàn)不同程度的不良反應(yīng)，主要為高血壓和/或低鉀血癥[56]。另一項應(yīng)用甘草酸苷治療急性發(fā)作性自身免疫性肝炎的研究發(fā)現(xiàn)，甘草酸苷經(jīng)靜脈給藥100 mg/d，在發(fā)病早期即可控制轉(zhuǎn)氨酶的水平，并且與甘草酸苷聯(lián)合皮質(zhì)醇治療組相比有更好的預(yù)后，而使用該劑量共4周的患者未出現(xiàn)明顯的不良反應(yīng)[57]?？梢姡什菟彳盏牟涣挤磻?yīng)是劑量和時間依賴性的，合理和適當(dāng)?shù)貞?yīng)用是比較安全和可耐受的。

3 展望

甘草因其和百藥解百毒，在中藥處方中最為常用。甘草酸苷是從甘草根部提取的主要活性成分。多年來，甘草酸苷制劑，如：復(fù)方甘草酸苷片、復(fù)方甘草酸苷注射劑等，在臨床上廣泛用于治療各種急、慢性炎癥和免疫性疾病，如病毒性肝炎、自身免疫性肝炎、肝硬化、濕疹、慢性蕁麻疹、銀屑病、斑禿、潰瘍性結(jié)腸炎等，其療效已經(jīng)得到肯定。隨著對其臨床應(yīng)用和作用機制的不斷深入研究，人們對甘草酸苷的認(rèn)識和使用將更為科學(xué)、有效和多樣。

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