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    消化道多巴胺及其代謝酶的功能研究

    來源:原創論文網 添加時間:2020-05-21

      摘    要: 多巴胺(dopamine, DA)是一種廣泛存在于中樞神經系統和外周組織的兒茶酚胺類神經遞質,其功能越來越受到學者們的關注,尤其是近年發現DA可以調節免疫系統功能,DA與腸黏膜炎癥相關疾病聯系的研究成為熱點。消化道是外周DA的重要來源,DA不僅產生于腸神經系統和消化道上皮等部位,而且還大量產自于腸道微生物。機體組織中DA的含量變化除了受其合成酶影響外,還受到兩個重要的代謝酶——單胺氧化酶(monoamine oxidase,MAO)和兒茶酚-O-甲基轉移酶(catechol-O-methyltransferase,COMT)的調控。本文主要對消化道DA的來源和功能、DA代謝酶的分布和功能進行綜述。

      關鍵詞: 消化道; 多巴胺; 單胺氧化酶; 兒茶酚氧位甲基轉移酶;

      Abstract: Dopamine(DA), as a catecholamine neurotransmitter widely distributed in the central nervous system and the peripheral tissues, has attracted a lot of attention. Especially in recent years, DA has been found to regulate the function of the immune system, and the involvement of DA in the intestinal mucosal inflammation-related diseases has become a hot research topic. The digestive tract is an important source of peripheral DA, and DA is not only produced in the enteric nervous system and gastrointestinal epithelium, but also produced by intestinal microorganisms. In addition to the synthetases of DA, the DA contents in body tissues are also affected by the two kinds of metabolic enzymes, monoamine oxidase(MAO) and catechol-O-methyltransferase(COMT). This article reviewed the sources, metabolism and functions of DA in digestive tract, especially focusing on the distribution and function of MAO and COMT, the enzymes degrading DA.

      Keyword: gastrointestinal tract; dopamine; monoamine oxidase; catechol-O-methyltransferase;

      多巴胺(dopamine,DA)是一種重要的單胺類神經遞質,不僅在中樞神經系統發揮調控運動、認知、情緒、記憶和獎賞等作用,在外周組織,尤其胃腸道中也發揮重要作用,包括保護胃腸黏膜[1,2],調節黏膜離子分泌[3,4],調節胃腸動力等[5,6,7,8,9]。近年來研究表明,DA還具有抑制神經炎癥[10]、系統性炎癥[11]、胰腺炎[12]、和腫瘤生長[13]等功能。除了存在于中樞神經系統和外周組織外,高濃度的DA在腸腔內容物中也被檢測出[14]。DA的快速降解保證了正常的突觸神經傳遞和胃腸功能的調節。單胺氧化酶(monoamine oxidase,MAO)和兒茶酚-O-甲基轉移酶(catechol-O-methyltransferase,COMT)是代謝DA的重要生物酶,在消化道分布廣泛。研究顯示,炎性腸病患者結腸黏膜DA含量顯著下降[15,16,17]。DA可以通過與自身受體結合影響結腸炎癥反應,其含量變化可能是炎性腸病發展的核心因素之一[18,19]。因此可以代謝DA、調控DA含量的MAO和COMT有可能成為治療胃腸道功能紊亂的新靶點。本文旨在綜述消化道DA的來源、功能,尤其代謝酶的分布和功能,為DA生理學、病理生理學與藥理學等研究提供參考。
     

    消化道多巴胺及其代謝酶的功能研究
     

      1、 DA的合成和代謝過程

      如圖1所示,酪氨酸在酪氨酸羥化酶(tyrosine Hydroxylase,TH,合成DA的限速酶)的作用下生成左旋多巴(levodopa,L-DOPA),后者經多巴脫羧酶(DOPA decarboxylase,DDC)脫羧生成DA。釋放到突觸間隙的DA大部分通過高親和力的DA轉運體(dopamine transporter,DAT)重攝取到突觸前神經元,少量的DA進入靜脈系統,但DA不能通過血腦屏障。此外,釋放的DA中的一小部分被DAT和其他低親和力轉運體,如有機陽離子轉運體1-3(organic cation transporter 1-3,OCT1-3)[20]和去甲腎上腺素轉運體(norepinephrine transporter,NET)轉入神經元外組織[21]。DA的快速降解確保了正常的突觸神經傳遞,對腸道運動和分泌的調節具有重要意義。MAO和COMT是兒茶酚胺和單胺類遞質的兩個重要代謝酶,此外醛脫氫酶也參與DA的代謝。DA的代謝有兩條途徑,一條是經過COMT生成3-甲氧酪氨(3-Methoxytyramine,3-MT),然后由MAO和醛脫氫酶代謝為高香草酸(homovanillic acid,HVA);另一條是先經過MAO代謝成3,4-二羥基苯乙醛(3,4-dihydroxyphenylacetaldehyde,DOPAL),然后醛脫氫酶將DOPAL轉化為3,4-羥基苯乙酸(3,4-hydroxy-phenylacetic acid,DOPAC),再經過COMT生成HVA。雖然存在不同的分解途徑,但DA代謝的最終產物是不具有生物活性的HVA[22]。有研究報道,神經突觸周圍細胞外液中的生理DA水平為1μm[23,24],血漿中DA的半衰期小于2 min,小鼠腦組織中DA的半衰期甚至更短[25],這可能是由于DA被MAO和COMT降解成了非活性代謝產物的緣故。

      圖1.多巴胺的合成和代謝過程
    圖1.多巴胺的合成和代謝過程

      Fig.1.The synthesis and metabolism progress of dopamine.TH:Tyrosine hydroxylase;L-DOPA:Levodopa;DDC:DOPA decarboxylase;DA:Dopamine;MAO:Monoamine oxidase;COMT:Catechol-O-methyltransferase;DOPAL:3,4-dihydroxyphenylacetaldehyde;AD:Aldehyde dehydrogenase;DOPAC:3,4-dihydroxyphenylacetic acid;3-MT:3-methoxytyramine;HVA:Homovanillic acid.

      2、 消化道DA的來源及功能

      研究報道機體約50%~70%的DA來源于消化道。胃、胰腺、腸神經系統、某些免疫細胞和腸道微生物都可以合成DA(圖2)。研究顯示,胰腺DA的濃度為10-7~10-5 mol/L,小腸為10-9~10-5 mol/L,結腸為10-8~10-4 mol/L,腸道微生物也含有高濃度DA,為10-7~10-4 mol/L,而循環系統中DA的濃度僅為10-11~10-8mol/L[26]。本研究組和其他學者都發現胃壁細胞表達TH和DAT,可以合成和分泌DA[27,28,29,30,31]。在胰腺,胰島細胞可以利用L-DOPA合成DA,但胰島并不表達TH,TH主要表達在外分泌腺泡細胞[32,33]。腸神經系統含有DA能神經元,可以合成和釋放DA[27]。研究也顯示,外周血或骨髓來源的多種免疫細胞,如調節性T細胞[34]、輔助T細胞[35]和樹突狀細胞[36]都表達TH,巨噬細胞、中性粒細胞[37]和B細胞[38]中也含有DA,但目前尚不明確消化道固有層的免疫細胞是否能合成DA。DA主要通過與受體結合來發揮作用,DA受體是G蛋白偶聯受體超家族的成員,包括D1、D2、D3、D4和D5。在消化道,DA與受體結合可參與多項胃腸功能的調節,包括:(1)調節胃酸和胃蛋白酶分泌。DA可以抑制基礎胃酸分泌[39],激動D2受體也可抑制組胺和卡巴膽堿誘導的胃酸分泌[40]。抑制D1受體和激活D2受體可顯著增加胃蛋白酶分泌[41,42]。(2)影響胃腸黏膜屏障。DA通過D1受體可抑制胃和十二指腸潰瘍的形成,而激動D2受體則具有促潰瘍作用[41]。本研究組前期研究顯示,激活D5受體可增加十二指腸黏膜的通透性[1],而激活結腸杯狀細胞膜上的D5受體可促進結腸黏液的合成和釋放[2]。(3)影響上皮細胞離子分泌。DA促進遠端結腸Cl-吸收與HCO3-分泌,此作用是通過β1和β2腎上腺素能受體介導[3,43],DA可通過D1受體介導的環磷酸腺苷(cyclic adenosinemonophosphate,cAMP)途徑促進十二指腸黏膜分泌K+[4]。(4)影響胃腸動力。DA可以抑制胃腸動力[44,45,46]。本研究組前期研究也顯示,DA分別通過作用于平滑肌上的D2受體和D1受體抑制胃和遠端結腸的動力[6,7]。DA還可以調節免疫穩態。D2受體激動劑可通過降低血管通透性及預防血管過度滲漏減輕潰瘍性結腸炎的嚴重程度[18]。D1受體激活可升高胞內cAMP,促進NLRP3炎癥小體(NLRP3 inflammasome)泛素化和降解,抑制NLRP3炎癥小體的活化,從而抑制脂多糖誘導骨髓源性巨噬細胞引起的系統性炎癥[11]。但腹腔注射小檗堿(一種廣泛的DA受體拮抗劑)可以抑制右旋糖酐硫酸鈉誘導的結腸炎小鼠腸系膜淋巴結釋放干擾素-γ和白介素17[47]。雖然上述研究表明DA可能通過不同受體對炎癥產生不一致的作用,但均提示DA具有免疫調節作用,關于胃腸DA能否直接作用于消化道的免疫細胞,從而發揮調控作用,還有待進一步研究。

      圖2.消化道多巴胺的來源
    圖2.消化道多巴胺的來源

      Fig.2.The sources of dopamine in the digestive tract.Dopamine is generated by gastric parietal cells,neurons of the enteric nervous system,pancreasβcells,certainmicroorganisms,and some immune cells of the intestinal lamina propria.

      近來的研究表明,腸腔內含有高濃度的DA[14],某些腸道細菌也可以合成DA,如蠟樣芽孢桿菌、枯草芽孢桿菌、普通變形桿菌、黏質沙雷氏菌、金黃色葡萄球菌、大腸桿菌和屎腸球菌等[48,49,50,51]。Shishov等在大腸桿菌培養液中檢測到納摩爾濃度的DA[49]。Villageliu等在體外模擬的小腸培養基中加入L-DOPA,結果顯示屎腸球菌可以利用L-DOPA產生DA[51]。此外,Asano等研究顯示,無特定病原體小鼠的腸腔中存在大量游離的、具有生物活性的DA,而無菌小鼠腸腔90%的DA呈無生物學活性的葡糖苷酸結合形式,梭狀芽孢桿菌具有較高的β-葡萄糖醛酸苷酶活性,可顯著升高無菌小鼠腸腔游離DA含量[14],提示某些細菌,特別是梭狀芽孢桿菌,可能有助于腸道中產生較多的游離DA。目前針對腸腔DA的功能研究較少,僅有報道腸腔內的DA可以促進回腸和結腸對水和電解質的吸收[52,53]。本研究組前期研究顯示,DA可以通過作用于結腸黏膜上皮杯狀細胞上的D5受體促進黏液的合成和釋放[2],也有文獻報道腸道微生物可以通過短鏈脂肪酸和脂多糖調節黏液合成或釋放,從而影響黏液屏障[54,55,56,57],但腸腔內DA是否參與腸道菌群對黏液屏障的調節目前并不清楚。此外,在潰瘍性結腸炎和克羅恩病中DA含量顯著下降[15,17],但發生機制并不清楚。最近一項研究顯示,腸腔內灌流選擇性D2和D3受體拮抗劑舒必利可以顯著減輕2,4-二硝基苯磺酸引起的結腸炎癥損傷[19],但此時舒必利的濃度達到毫摩爾水平,其可能會通過阻滯DA受體以外的藥理機制發揮抗炎作用,腸腔內DA是否能影響炎性腸病的炎癥程度仍需進一步研究。多項研究表明腸道菌群與腸炎的誘發和加劇相關[58,59],微生物產生的生物活性物質可能作為宿主和細菌之間的共同語言,實現雙向交流。DA可通過D2和D3受體激活T細胞,分泌白介素2、干擾素-γ和白介素4,而服用屎腸球菌也可升高這幾種炎癥因子的水平[60,61],DA對炎癥因子的一些影響與口服屎腸球菌的作用重疊,因此我們推測通過產生DA來調節炎癥可能是屎腸球菌發揮作用的機制之一,但產生DA的益生菌,如屎腸球菌和芽孢桿菌等是否是通過產生DA作用于免疫細胞,從而調節腸道炎癥等病理過程仍需進一步研究。

      3、 消化道DA代謝酶的分布和功能

      3.1、 MAO

      MAO是線粒體黃素蛋白酶,存在于線粒體外膜,其可以催化生物源性和外源性的胺氧化成相應的醛。MAO主要降解單胺類激素和神經遞質,如腎上腺素、去甲腎上腺素、5-羥色胺、酪胺、苯乙胺和DA。在哺乳動物體內MAO分為兩種亞型:MAO-A和MAO-B。它們由兩個獨立的基因編碼,70%的氨基酸序列具有同一性[62]。在正常生理條件下MAO-A優先氧化5-羥色胺和酪胺,而MAO-B優先選擇苯乙胺作為底物。作為DA重要的代謝酶,MAO-A和MAO-B均參與代謝DA,并在消化道組織中有廣泛表達(表1)。

      表1.單胺氧化酶(MAO)-A和MAO-B在消化道的表達
    表1.單胺氧化酶(MAO)-A和MAO-B在消化道的表達

      3.1.1、黏膜層的MAO

      在胃體,MAO-B存在于基底部的泌酸黏膜,并且和組氨酸脫羧酶陽性的細胞共存,可能和組胺滅活和胃酸分泌調節有關[63]。在人十二指腸,兩種亞型MAO在絨毛、隱窩和肌層含量都比較豐富,而黏膜下層的表達較低。MAO-A大量存在于絨毛和隱窩,而MAO-B強陽性反應只存在于絨毛[64,65,66]。在消化道,MAO-A的活性約占MAO總活性的80%,顯著高于MAO-B的活性[9,64,67,68](表2)。MAO可以降解攝入消化道中的膳食胺,因而對于具有潛在毒性的一些胺類物質,如酪胺等具有分解和去除毒性的作用[69],因此服用MAO-A抑制劑后,若攝入能使擬交感神經興奮的胺類可能會產生致命的高血壓危象,而MAO-B抑制劑無此副作用[70,71]。此外,結腸腔內容物DA的濃度略高于結腸組織,而循環系統中DA的濃度更低[26]。有文獻報道回腸原代上皮細胞具有MAO活性,可代謝外源性的DA[68]。Caco-2細胞系(人腸上皮細胞系)頂膜側的5-羥色胺轉運體可以轉運外源性5-羥色胺進入細胞[72]。本研究組前期研究顯示,大鼠結腸上皮細胞的頂膜側也表達DAT[31],提示腸腔內DA可能被DAT轉運到結腸上皮細胞,而DA的代謝酶MAO在結腸上皮細胞也有表達,提示結腸黏膜中的MAO可以降解從腸腔轉運到上皮細胞中的DA,從而維持內源性DA的穩態。以上研究提示,消化道黏膜的MAO可能是抵抗外源性胺類的一道屏障。雖然MAO在胃腸道的表達超過了其在中樞的表達水平,但人們目前對MAO在消化道中的作用卻知之甚少。

      表2.單胺氧化酶(MAO)在消化道的活性
    表2.單胺氧化酶(MAO)在消化道的活性

      3.1.2、腸神經叢的MAO

      MAO-A和MAO-B在中樞神經系統中分布廣泛,MAO-A主要存在于兒茶酚胺能神經元,MAO-B主要存在于5-羥色胺和組胺能神經元,以及星形膠質細胞[73]。本研究組之前的研究結果表明,MAO-A和MAO-B在大鼠和人的結腸肌間神經叢有表達[9](圖3)。與之前在中樞神經系統中的結果類似,MAO-B在神經微絲(neurofilament,NF)陽性的神經元和膠質纖維酸性蛋白(glial fibrillary acidic protein,GFAP)陽性的膠質細胞中有表達,而MAO-A只在NF陽性神經元中觀察到,而不表達在GFAP陽性膠質細胞中。大多數GFAP陽性細胞表達MAO-B,但只有一小部分NF陽性神經元具有MAO-B。在大鼠結腸,與MAO-B共存的NF和GFAP陽性細胞所占的百分比分別約為17%和83%;人結腸中的比例與大鼠相似,分別約為26%和75%;而在大鼠和人的結腸中NF陽性細胞表達MAO-A的百分比分別為52%和30%[9]。研究表明,中樞神經系統的MAO-B活性上調可升高帕金森病(Parkinson’s disease,PD)的發病風險[74,75]。此外,中樞星形膠質細胞中的MAO-B可將1-甲基-4-苯基-1,2,3,6-四氫吡啶(MPTP)轉化為毒性代謝物1-甲基-4-苯基吡啶(MPP+),MPP+可選擇性地破壞黑質DA能神經元[76]。MPTP腹腔注射也能損毀外周DA能系統[77,78],并誘導小鼠腸道中TH神經元表達和DA水平的選擇性降低[77,79]。而腸膠質細胞也表達MAO-B,提示MPTP在腸道中也能轉化為MPP+,從而損傷腸道的功能,這可能是MPTP小鼠腸道DA含量降低和腸動力受損的原因之一[77,78,79]。本研究組前期研究也顯示,MPTP小鼠胃黏膜、十二指腸、結腸TH的表達顯著降低[30],提示MAO-B可能在全消化道的膠質細胞中都有表達。

      圖3.單胺氧化酶(MAO)-A和MAO-B在大鼠和人結腸肌間神經叢和肌層的分布
    圖3.單胺氧化酶(MAO)-A和MAO-B在大鼠和人結腸肌間神經叢和肌層的分布

      3.1.3、消化道平滑肌的MAO

      MAO-A和MAO-B在十二指腸和結腸的肌層都有表達(表1)。本研究組研究顯示,大鼠結腸肌層中MAO-B蛋白表達顯著高于黏膜層,而MAO-A蛋白表達并無顯著差異[9]。平滑肌中的MAO可能通過影響單胺神經遞質(如DA)的水平影響結腸動力與轉運。由于MAO-B抑制劑可以抑制DA代謝,目前MAO-B抑制劑已經成為治療PD的重要藥理學靶點,常用的藥物為雷沙吉蘭(rasagiline)和沙芬酰胺(safinamide)。雷沙吉蘭是第二代選擇性、不可逆的MAO-B抑制劑[80,81]。沙芬酰胺是第三代選擇性、可逆性MAO-B抑制劑,并且還具有抑制谷氨酸的釋放的作用。此外,雷沙吉蘭和沙芬酰胺都具有神經保護作用[82,83]。在臨床應用時,雷沙吉蘭在PD早期階段可作為單一療法使用,緩解疾病進程,或在PD的晚期階段使用,輔助L-DOPA改善運動癥狀[84,85]。當作為L-DOPA的輔助用藥或與其他PD藥物聯合使用時,沙芬酰胺增加每日“打開”時間,顯著改善中晚期波動性PD患者的運動癥狀和生活質量[86]。但也有臨床報道,長期聯合使用L-DOPA和MAO-B抑制劑(雷沙吉蘭和沙芬酰胺)后,PD患者出現便秘癥狀的幾率增加[87,88,89]。本研究組研究顯示,雷沙吉蘭給藥4周可通過抑制大鼠結腸MAO-B活性減少DA代謝,升高結腸DA水平,抑制結腸動力[5,6,7]。DA可以通過與其D1受體結合抑制結腸動力,延長結腸轉運時間[5,6],通過D2受體抑制胃動力與胃排空[7,45]。這可以解釋為什么長期使用雷沙吉蘭的PD患者便秘風險可能會有增加。

      3.2、 COMT

      COMT在二價金屬Mg2+離子的存在下可以催化甲基基團從S-腺苷甲硫氨酸轉移到兒茶酚胺類神經遞質上,其底物包括L-DOPA、DA、腎上腺素和去甲腎上腺素等。COMT存在兩個亞型:膜結合性COMT(MB-COMT)和可溶性COMT(S-COMT),兩個亞型的COMT由同一個基因編碼。S-COMT存在于胞質溶膠中,是COMT的主要形式,被認為在消除外源性生物活性或毒性的兒茶酚胺和一些羥基化代謝物中扮演更重要的角色;MB-COMT是一種微粒體蛋白,定位于粗面內質網,在兒茶酚胺生理低濃度時發揮作用,可終止DA和去甲腎上腺素的突觸傳遞[90]。因此,在腸黏膜和大腦中,COMT也作為血液和其它組織之間的解毒屏障,屏蔽外源化學物質的有害影響[91]。

      3.2.1、黏膜層的COMT

      消化道上皮細胞廣泛表達COMT[92,93](表3),如胃體、幽門、十二指腸、回腸和結腸。研究報道,胃體和幽門上皮細胞表達COMT,小鼠十二指腸上皮細胞和微絨毛中也存在COMT,但在胃腸道的內分泌細胞則并未見COMT的表達[94]。MB-COMT和S-COMT在不同區域的活性不同[68,92](表4)。在大鼠小腸,S-COMT是黏膜和肌層中COMT的主要形式,并且S-COMT活性在十二指腸黏膜層最高,空腸和回腸黏膜層稍低。而MB-COMT的活性在黏膜和肌層以及胃腸道的不同區域幾乎相等。L-DOPA的主要吸收部位是十二指腸和空腸,而胃腸道黏膜中COMT的高表達和活性可能有助于兒茶酚如L-DOPA的代謝[92]。COMT抑制劑可防止L-DOPA在外周組織轉化為3-O-甲基多巴,上調外周L-DOPA水平,因而進入到中樞的L-DOPA增多,DA的合成增加。此外,進入中樞的COMT抑制劑可通過降低L-DOPA和DA的代謝,進一步提高L-DOPA的利用度和DA的含量,因此COMT的抑制劑成為治療PD患者的輔助藥物,在臨床上廣泛應用。據報道,切除肝臟的大鼠其血漿或其他組織中3-O-甲基多巴的水平沒有降低[92],提示消化道的COMT在外源性兒茶酚的代謝中發揮著重要作用。回腸原代上皮細胞的COMT被證明可代謝外源性的DA[68],而結腸內容物含有高濃度的DA[14],結腸上皮細胞的頂膜側也表達DAT[30],因此我們推測結腸黏膜中的COMT可能也參與維持內源性DA的穩態,降解從腸腔轉運到上皮細胞中的DA。

      表3.兒茶酚氧位甲基轉移酶(COMT)在消化道的分布。
    表3.兒茶酚氧位甲基轉移酶(COMT)在消化道的分布。

      表4.兒茶酚氧位甲基轉移酶(COMT)在消化道的活性
    表4.兒茶酚氧位甲基轉移酶(COMT)在消化道的活性

      3.2.2、腸神經叢和平滑肌的COMT

      在中樞神經系統,COMT在神經元和神經膠質細胞中有表達,并且神經元中COMT mRNA水平明顯高于神經膠質細胞[95]。在人和大鼠的中腦DA能神經元中均檢測到COMT mRNA[95],但COMT在腸神經系統中的分布目前尚未見報道,并且其在肌層的表達研究也較少。在人小腸各部位的肌層,MB-COMT的活性相差不大,但S-COMT活性在十二指腸最高,其次是空腸,回腸最低[92](表4)。COMT抑制劑在臨床應用時存在誘發腹瀉等副作用,有時甚至發生在開始治療后兩至四個月[96]。本研究組前期研究顯示,COMT抑制劑恩他卡朋可能通過促進結腸上皮細胞分泌Cl-,從而引起腹瀉[97]。此外,本研究組研究顯示,恩他卡朋以劑量依賴性的方式抑制離體結腸縱行肌的自發收縮,這種抑制作用可被β2腎上腺素受體拮抗劑阻斷67%[98],提示恩他卡朋抑制結腸動力可能是β2腎上腺素受體介導的。但COMT是否能通過影響單胺神經遞質(如DA)的水平來影響結腸動力尚未見報道。

      4 、小結

      除中樞神經系統以外,消化道是機體DA不可忽視的重要來源地。消化道分布著大量的MAO和COMT,對于調控消化道DA的含量和功能發揮著重要作用。腸道微生物可以產生DA,許多疾病如腸易激綜合征、炎癥性腸病以及代謝性疾病和神經退行性疾病等均表現有腸道微生物群的改變,DA在其中扮演何種角色,功能意義如何,這些問題有待進一步的研究。’

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