郭長征 馮泮飛 毛勝勇

(江蘇省消化道營養(yǎng)與動物健康重點實驗室，南京農業(yè)大學消化道微生物實驗室，南京210095)

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槲皮素的藥理作用機制及其在奶牛生產中的應用

郭長征 馮泮飛 毛勝勇*

(江蘇省消化道營養(yǎng)與動物健康重點實驗室，南京農業(yè)大學消化道微生物實驗室，南京210095)

槲皮素是中草藥和果蔬等植物中常見的黃酮醇類物質，具有抗炎、抗菌、抗氧化、抗腫瘤及抗癌等廣泛的藥理活性。近年來在奶牛研究中發(fā)現(xiàn)，槲皮素可改善奶牛瘤胃發(fā)酵，對奶牛糖代謝及脂代謝具有一定影響。本文就槲皮素的藥理作用機制及其在奶牛生產中的應用進展進行了綜述，擬為槲皮素的進一步開發(fā)應用提供理論參考。

槲皮素；生物學作用；機制；奶牛

在現(xiàn)代集約化養(yǎng)殖業(yè)中，為最大程度地追求生產效益，在奶牛生產中常使用高比例精料[1]；較高的能量攝入及較高的產奶量使奶牛機體氧化代謝增強，進而產生大量活性氧[2-3]，造成機體出現(xiàn)氧化損傷。另外，我國南方夏季炎熱高溫引發(fā)的奶牛熱應激問題也常導致動物自身的抗氧化能力下降[4-5]，并對奶牛生產性能、繁殖性能及免疫性能等造成不利影響[6-8]。因此，如何提高動物抗氧化能力已成為當前奶牛生產的一個重要問題。槲皮素(quercetin，3，3’，4’，5，7-五羥基黃酮，圖1)是植物界中分布最廣的黃酮類化合物，可減少嚙齒動物肝脂肪積聚預防脂肪肝發(fā)生[9-10]，同時具有抗氧化、抗炎功能[11-12]。因此，一些研究者認為，開發(fā)基于槲皮素為基礎的飼料添加劑對保障奶牛健康具有重要意義。本文在前人研究基礎上，綜述了槲皮素的藥理作用機制及在奶牛生產上應用的初步進展，擬為槲皮素的應用開發(fā)提供理論參考。

1 槲皮素的藥理作用及機制

1.1 槲皮素的抗炎作用及機制

研究發(fā)現(xiàn)，一些經(jīng)典的炎性相關疾病如(類)風濕性關節(jié)炎、動脈粥樣硬化和全身性炎癥反應綜合征等急慢性炎性疾病的發(fā)生或致病過程，均與核轉錄因子κB(NF-κB)過度或持續(xù)激活密切相關[13]。NF-κB可誘導細胞因子、趨化因子、黏附分子[如細胞間黏附分子-1(ICAM-1)、血管細胞黏附分子-1(VCAM-1)和內皮白細胞黏附分子1(ELAM1)]大量生成，同時激活一些與炎性級聯(lián)放大相關的酶[如誘導型一氧化氮合酶(iNOS)和誘導型環(huán)氧化合酶]。Cho等[14]研究表明，槲皮素可抑制細胞外信號調節(jié)激酶(ERK)和p38絲裂原活化蛋白激酶(p38MAPK)的磷酸化，且通過穩(wěn)定核轉錄因子κB/核轉錄因子κB抑制蛋白復合體(NF-κB/IκB)阻止核轉錄因子κB抑制蛋白(IκB)的脫落，抑制下游白細胞介素-1β(IL-1β)、白細胞介素-6(IL-6)、腫瘤壞死因子-α(TNF-α)及一氧化氮(NO)/iNOS的表達。Min等[15]發(fā)現(xiàn)，槲皮素可封阻p38MAPK和NFκB的活化，減少IL-1β、IL-6、TNF-α和白細胞介素-8(IL-8)的表達。此外，槲皮素可在轉錄和蛋白質水平抑制前炎癥因子誘導VCAM-1、ICAM-1和單核細胞趨化蛋白(MCP-1)的表達與合成[16]；抑制激活蛋白-1的活性和c-Jun氨基末端激酶(JNK)通路，減少佛波酯和TNF-α誘導人類內皮細胞ICAM-1的產生[17]。有研究顯示，槲皮素還可抑制iNOS和環(huán)氧化合酶-2(COX-2)的表達[18-21]。槲皮素亦可抑制免疫細胞組胺酸脫羧酶的翻譯[22]、組胺釋放[23]及脫粒[24]。

圖1 槲皮素的化學結構

1.2 槲皮素的抗氧化作用及機制

動物機體在代謝營養(yǎng)物質時，可產生大量自由基，正常情況下，自由基可被體內的防御體系清除；但當機體受損時，自由基可引起細胞薄膜脂質過氧化，導致細胞薄膜損傷，改變滲透壓引起細胞腫脹，最終導致細胞死亡[25]。體內自由基的來源包括酶促反應與非酶促反應產生2種途徑。酶促反應途徑中，黃嘌呤氧化酶(XO)、脂氧化酶(LOX)、醛氧化酶(AO)等均為可催化產生自由基的氧化酶；非酶促反應途徑是體內某些物質的自動氧化與分子氧的單電子還原途徑，自動氧化如過渡金屬離子的氧化還原及過氧化物均可產生自由基。目前發(fā)現(xiàn)，槲皮素可通過抑制自由基的產生、防止脂質過氧化、激活機體抗氧化體系等方式起到抗氧化作用。

1.2.1 抑制自由基的產生

研究表明，槲皮素可通過抑制黃嘌呤氧化酶活而抑制超氧化物產生[26-27]。Ratty等[28]用抗壞血酸維生素C和硫酸亞鐵誘導小鼠腦線粒體脂質過氧化，探究槲皮素的抑制效應，結果表明，槲皮素可同時抑制前述2種誘導劑誘導脂質過氧化。

1.2.2 激活機體抗氧化體系

體內的抗氧化酶有超氧化物歧化酶(SOD)、谷胱甘肽過氧化物酶(GSH-Px)和過氧化氫酶(CAT)等。Coskun等[29]以鏈脲霉素誘導小鼠糖尿病為模型研究槲皮素添加效應，結果表明，小鼠注射鏈脲霉素可引起脂質過氧化，顯著降低谷胱甘肽過氧化物酶、超氧化物歧化酶、過氧化氫酶活性，而槲皮素則顯著提高了上述抗氧化酶的活性。

1.3 槲皮素的抗腫瘤作用及機制

1.3.1 抑制腫瘤細胞增殖

槲皮素對多種惡性腫瘤細胞均有抑制作用，如胃癌細胞(HGC-27、NUGE-2、MKN-7、MKN-28)[30]、結腸癌細胞(COLO320 DM)[30-31]、人乳癌細胞[31-32]、人鱗狀細胞和膠質瘤細胞[33-34]、卵巢癌細胞[35]、人肝癌細胞和人胰腺癌細胞[32,36]。腫瘤細胞即使在氧供應充分的條件下，仍以糖酵解方式獲取能量，稱為有氧糖酵解，這既是著名的“Warburg效應”。槲皮素抑制腫瘤細胞增殖的原因可能是阻止了腫瘤細胞有氧糖酵解[37]。

1.3.2 誘導腫瘤細胞凋亡

有研究表明，槲皮素可通過激活內部線粒體途徑促進腫瘤細胞凋亡。當細胞受到內部凋亡刺激因子作用，凋亡因子Bax、Bak等受到激活結合到線粒體外膜，在膜上形成線粒體內部通向胞質的孔道，致使細胞色素C等進入細胞質。細胞色素C激活凋亡酶激活因子-1(APAF-1)，APAF-1可活化含半胱氨酸的天冬氨酸蛋白水解酶-9(caspase-9)。細胞色素C、APAF-1、caspase-9組成凋亡小體，該凋亡小體具有裂解凋亡蛋白酶含半胱氨酸的天冬氨酸蛋白水解酶-7(caspase-7)的作用，caspase-7裂解激活后引起下游與細胞生命相關蛋白質的降解，最終引起細胞凋亡。B淋巴細胞瘤-2(Bcl-2)、髓樣細胞白血病-1(Mcl-1)、B淋巴細胞瘤-xL(Bcl-xL)可通過抑制Bax、Bak作用，發(fā)揮抗凋亡作用[38]。研究表明，槲皮素可下調多種癌細胞Bcl-2、Mcl-1、Bcl-xL水平，上調Bax水平，并激活下游通路，促進細胞凋亡，從而起到抗腫瘤作用[39-47]。

1.3.3 抑制腫瘤細胞轉移、侵襲

腫瘤侵襲和轉移的關鍵步驟是降解腫瘤周圍的基質，基質金屬蛋白酶(MMP)能通過破壞基質的降解平衡，進而促進癌細胞突破基底膜和細胞外基質構成的組織學屏障，從而侵襲周圍組織和轉移至遠處組織。有研究表明，槲皮素可通過蛋白激酶C(PKC)通路下調基質金屬蛋白酶前體-9(Pro-MMP-9)[48]；減少MMP-2、MMP-9的分泌[32,36]；抑制MMP-2、MMP-9的活性[49]，從而抑制癌細胞的侵襲。

2 槲皮素在奶牛生產上的應用進展

2.1 槲皮素的生物利用率

奶牛不同于單胃動物，其瘤胃內棲息著各種微生物，包括瘤胃原蟲、瘤胃細菌、和厭氧真菌，還有少數(shù)噬菌體[50]。槲皮素是否能夠有效進入奶牛外周循環(huán)，是其在奶牛上能否發(fā)揮出在單胃動物上功能的前提。通過瘤胃瘺管添加槲皮素的動力學試驗表明，總黃酮醇(結合與非結合形式槲皮素及結合與非結合形式的槲皮素衍生物之和)的絕對生物利用率僅為0.1%[51]。有研究表明，槲皮素被瘤胃微生物迅速降解成3，4-二羥基苯乙酸和4-甲基鄰苯二酚[52]，這可能是生物利用率低的原因。而通過奶牛十二指腸添加槲皮素接近豬等單胃動物口服添加下的生物利用率[53]。因此，過瘤胃添加槲皮素更能發(fā)揮其在奶牛生產中的作用。

2.2 槲皮素對瘤胃發(fā)酵的影響

槲皮素對變異鏈球菌、血鏈球菌、嗜酸乳桿菌和遠緣鏈球菌有抑制效應[54]，暗示其可能通過改變瘤胃微生物菌群從而調控瘤胃發(fā)酵。瘤胃是反芻動物消化代謝和營養(yǎng)物質吸收最重要的場所，飼糧中碳水化合物在瘤胃內被瘤胃微生物發(fā)酵產生揮發(fā)性脂肪酸(VFA)，VFA可為宿主提供60%～80%的能量[55]。瘤胃發(fā)酵體外模擬試驗表明，添加不同劑量槲皮素瘤胃發(fā)酵參數(shù)不一致。添加500 mg/L槲皮素可顯著增加總揮發(fā)性脂肪酸(TVFA)濃度[56]，作者認為槲皮素刺激了瘤胃發(fā)酵。其他研究表明，添加量為4.5%底物時，槲皮素對pH、TVFA濃度、單一VFA比例無顯著影響[57]；槲皮素對干物質降解率及羧甲基纖維素酶、木聚糖酶、β-葡萄糖苷酶活性無顯著影響，說明槲皮素并不能改變瘤胃對營養(yǎng)物質的發(fā)酵程度[57]；另外，最近的研究表明，槲皮素可被瘤胃微生物迅速降解，通過奶牛瘤胃瘺管添加50 mg/kg BW的槲皮素對TVFA濃度及各單一VFA比例也無顯著影響[52]。此外，與體外發(fā)酵相比，瘤胃添加槲皮素被快速吸收入血液或降解；而體外發(fā)酵槲皮素不能向腸道外流。因此，部分研究中添加槲皮素顯著增加TVFA濃度的結果，可能是槲皮素被瘤胃微生物降解利用造成的。

有研究認為，對于減少甲烷產生，植物次級代謝物相比于離子載體和益生菌具有價格低廉及環(huán)保的優(yōu)勢[58]，具有作為抑制甲烷產生的添加劑的潛力，槲皮素是其中分布最廣的類黃酮[59]。目前體外發(fā)酵試驗表明，槲皮素添加量為4.5%底物時，可增加產氣量，減少甲烷產量，降低原蟲、產甲烷菌數(shù)量[57]；培養(yǎng)基中添加100 μmol/L的槲皮素對產氣量及甲烷產量無顯著影響[52]。結果不一可能是試驗條件及添加量不同所致。Leiber等[60]研究發(fā)現(xiàn)，添加蘆丁(5和500 μmol/L的槲皮素)可顯著增加產氣量，但是其中甲烷比例下降，作者認為蘆丁被非產甲烷微生物作為底物產生CO2，從而降低了總產氣中甲烷的比例。綜上，槲皮素對于產氣量和甲烷含量的影響及機制還需進一步研究確定；槲皮素對除原蟲、產甲烷菌外的瘤胃微生物無抑制作用。

2.3 槲皮素對奶牛機體健康的影響

圍產期奶牛采食攝入的能量不足以滿足泌乳需要，奶牛動用體脂供能，當肝臟吸收的脂質超過其氧化和分泌時發(fā)生脂肪肝[1]。有研究表明，約有50%的奶?？砂l(fā)生脂肪肝同時伴隨肝細胞損害及肝功能下降[61-62]。另外，由于圍產期奶牛大量的能量攝入及泌乳造成氧化代謝增強，產生更多活性氧[2-3]。研究發(fā)現(xiàn)，槲皮素可減少嚙齒動物肝臟脂肪積聚及預防脂肪肝發(fā)生[10]。由此，結合槲皮素的保肝作用及抗炎、抗氧化作用，一些學者對槲皮素在奶牛上的作用進行了初步研究。連續(xù)28 d通過十二指腸瘺管添加36 mg/kg BW的槲皮素對奶牛超氧化物歧化酶、谷胱甘肽過氧化物酶和過氧化氫酶活性均無顯著影響[63]。原因可能在于以下2點：1)槲皮素添加劑量少，添加100 mg/kg BW的槲皮素在mRNA水平上顯著提高了奶牛超氧化物歧化酶表達量[64]；2)槲皮素的抗氧化作用與機體健康程度有關，槲皮素對鏈霉素誘導的糖尿病、人造肝臟損傷有積極作用[65-67]，而對健康小鼠超氧化物歧化酶和過氧化氫酶活性無影響[68]。

槲皮素可提高血液中胰島素含量，降低葡萄糖含量，與在人糖尿病中的作用一致[69]。但是對于糖代謝相關基因(葡萄糖6磷酸酶、丙酮酸羧化酶和磷酸烯醇式丙酮酸羧化酶)則無顯著影響。有報道表明，槲皮素可抑制腸細胞對葡萄糖的吸收而提高肌細胞的吸收[70-71]。因此槲皮素可能通過促進胰島素的分泌及其他組織對葡萄糖的吸收降低血液葡萄糖含量。

重度脂肪浸潤可導致肝細胞破壞，隨后引起胞漿天冬氨酸轉氨酶釋放[69]。谷氨酸脫氫酶主要存在于肝臟中，其血液中含量升高暗示肝細胞死亡或亞致死損傷[72]。有研究表明，槲皮素可顯著降低奶牛血液中天冬氨酸轉氨酶含量，雖然血液中谷氨酸脫氫酶含量統(tǒng)計學上變化不顯著，但是未添加槲皮素奶牛分娩后比分娩前谷氨酸脫氫酶含量增加了300%，而添加槲皮素奶牛僅增加了50%[73]。此結果表明，槲皮素具有減少肝損害的作用。另外，槲皮素具有減少肝臟脂肪含量的趨勢[64]。因此，槲皮素可能通過減少肝細胞損害，保護肝細胞的正常功能而減少肝臟脂肪含量。

2.4 槲皮素對奶牛生產性能及蹄部健康的影響

飼糧中添加槲皮素可提高泌乳中期奶牛的乳蛋白含量，但對乳脂、乳糖含量無影響[63]。作者認為這可能與槲皮素增加血液中胰島素含量有關。有研究表明，靜脈灌注胰島素可提高奶牛乳蛋白含量[74]。而在奶牛瘤胃中長期灌注蘆丁(槲皮素糖苷衍生物)，可使奶牛產奶量提高10.06%，但對乳品質無顯著影響[75]。

MMP主要功能是降解細胞外基質和基膜，奶牛蹄組織中存在MMP，在健康狀況下，MMP基因的表達及活性均受到嚴格的調控，但在亞急性瘤胃酸中毒條件下，奶牛蹄組織中MMP-2和MMP-9的活性上調，進而催化降解基膜等重要結構，使蹄葉組織失去正常的連接、滲透與屏障功能，最終導致真皮小葉與角小葉發(fā)生滲出性炎癥，形成蹄葉炎[76]。槲皮素抗腫瘤作用中顯示，槲皮素可抑制MMP-2和MMP-9上游通路，阻止其分泌并抑制其活性。因此，槲皮素可能具有預防蹄葉炎的作用。但在奶牛上的研究發(fā)現(xiàn)，槲皮素對MMP-2和MMP-9表達無顯著影響，僅對奶牛蹄白線分離有改善作用[77]。原因可能是，槲皮素對MMP-2和MMP-9抑制基本為離體試驗，而奶牛上的研究中槲皮素添加形式為口服，槲皮素可能被瘤胃微生物降解造成生物利用率低。因此，未來有必要開展蹄組織體外培養(yǎng)的研究，以確定槲皮素是否具有預防蹄葉炎的作用，以期為研究有效的過瘤胃槲皮素奠定基礎。

3 小 結

槲皮素是黃酮類化合物中一種天然植物提取物，具有抗炎、抗氧化及抗腫瘤等功能。槲皮素在奶牛生產上的研究還處于初步階段，對抑制甲烷產生、減少肝臟脂肪積聚、減少肝損傷、提高乳蛋白含量及預防蹄葉炎方面體現(xiàn)出較大潛力。但是由于槲皮素可被瘤胃微生物降解且上述試驗中試驗動物偏少，因此開發(fā)過瘤胃形式槲皮素、開展大規(guī)模動物試驗進一步驗證槲皮素在奶牛生產上的作用很有必要。

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*Corresponding author, professor, E-mail： maoshengyong@163.com

(責任編輯 王智航)

Quercetin: Pharmacological Action Mechanism and Application in Dairy Cows Production

GUO Changzheng FENG Panfei MAO Shengyong*

(JiangsuKeyLaboratoryofGastrointestinalNutritionandAnimalHealth,LaboratoryofGastrointestinalMicrobiology,NanjingAgriculturalUniversity,Nanjing210095,China)

Quercetin is a common flavonoid in herbs, fruits and vegetables, and has anti-inflammatory, antibacterial, antioxidant, anti-tumor and anti-cancer and other pharmacological activities. In recent years, studies found that quercetin addition could improve rumen fermentation of dairy cows, and could affect glucose metabolism and lipid metabolism. In this paper, the pharmacological mechanism of quercetin and its application in dairy cows production were reviewed to provide reference for the further development and application.[ChineseJournalofAnimalNutrition, 2017, 29(1)：42-49]

quercetin; biochemical function; mechanism; dairy cow

10.3969/j.issn.1006-267x.2017.01.006

2016-07-12

國家自然科學基金項目(31372339)

郭長征(1992—)，男，河南濮陽人，碩士研究生，從事反芻動物營養(yǎng)研究。E-mail: 2014105044@njau.edu.cn

*通信作者：毛勝勇，教授，博士生導師，E-mail： maoshengyong@163.com

S816.7；S823

A

1006-267X(2017)01-0042-08