炎癥性疾病中細(xì)胞色素P450表達(dá)調(diào)控的研究進(jìn)展

虞 茜，李 巍

(1. 揚州大學(xué)醫(yī)學(xué)院 基礎(chǔ)醫(yī)學(xué)系，江蘇 揚州 225001； 2. 揚州大學(xué)醫(yī)學(xué)院 臨床醫(yī)學(xué)系，江蘇 揚州 225001；3. 江蘇省中西醫(yī)結(jié)合老年病防治重點實驗室，江蘇 揚州 225001)

綜 述

炎癥性疾病中細(xì)胞色素P450表達(dá)調(diào)控的研究進(jìn)展

虞 茜1，李 巍2，3

(1. 揚州大學(xué)醫(yī)學(xué)院 基礎(chǔ)醫(yī)學(xué)系，江蘇 揚州 225001； 2. 揚州大學(xué)醫(yī)學(xué)院 臨床醫(yī)學(xué)系，江蘇 揚州 225001；3. 江蘇省中西醫(yī)結(jié)合老年病防治重點實驗室，江蘇 揚州 225001)

細(xì)胞色素P450(cytochrome P450, CYPs)是人體內(nèi)催化外源化合物氧化反應(yīng)的主要代謝酶，參與了近90%藥物的代謝。在炎癥性疾病過程中，CYPs家族某些成員的表達(dá)可能會下降從而改變藥物的代謝表型，對CYPs的誘導(dǎo)或抑制可能改變藥物代謝速度，進(jìn)而影響體內(nèi)藥物的濃度。而在此過程中影響CYPs的機(jī)制可能與Th1細(xì)胞分泌的IL-1β、IL-2、IL-6、TNF-α、IFN-γ，Th2細(xì)胞分泌的IL-4、IL-5、IL-10、IL-13、TGF-β，核受體和microRNA有關(guān)。本文綜述炎癥性疾病中CYPs的調(diào)節(jié)作用及相關(guān)機(jī)制，為炎癥性疾病臨床用藥提供參考。

細(xì)胞色素P450；炎癥；細(xì)胞因子；疾病；感染

細(xì)胞色素P450(cytochrome P450, CYPs)是一類混合功能氧化酶，主要存在于肝細(xì)胞光面內(nèi)質(zhì)網(wǎng)內(nèi)。人類編碼的CYPs基因分屬于18個基因家族的44個亞家族，其中涉及體內(nèi)大多數(shù)藥物代謝的主要為前3個基因家族(CYP1、CYP2、CYP3)中的7個重要的亞型，分別為CYP1A1、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4[1]?；贑YPs代謝的藥物不僅可作為CYPs的底物，還能作為CYPs的酶誘導(dǎo)劑或者抑制劑， CYPs酶活性被誘導(dǎo)或抑制能加速或者減緩CYPs底物代謝，引發(fā)其底物血藥濃度的改變，從而影響藥物的安全性和有效性。近期研究表明由藥物代謝改變導(dǎo)致藥物不良反應(yīng)占住院病例的10%[2]。影響CYPs活性的因素包括遺傳、年齡和共服藥物等。近年來疾病導(dǎo)致的CYPs活性變化引發(fā)的不良反應(yīng)也開始受到關(guān)注[2-4]。Woolbright BL等[5]研究表明機(jī)體在炎癥和感染的情況下肝臟內(nèi)CYPs的表達(dá)和酶活性會受到影響。其中最先報道的研究是在小兒流感過程中，炎性細(xì)胞因子水平的升高引起CYPs表達(dá)降低，導(dǎo)致茶堿的清除降低，血藥濃度升高，半衰期延長，引發(fā)了茶堿過量癥狀的出現(xiàn)[6]。因此，了解炎癥條件下CYPs的調(diào)節(jié)作用及機(jī)制，可對臨床合理用藥，避免藥物-疾病相互作用提供參考。

研究發(fā)現(xiàn)，感染細(xì)菌、病毒及寄生蟲引發(fā)的炎癥以及類風(fēng)濕性關(guān)節(jié)炎等炎癥性疾病均對CYPs的表達(dá)有調(diào)控作用[2-3,7]。這些炎癥反應(yīng)又分為1型免疫和2型免疫，分別由Th1和Th2細(xì)胞為主介導(dǎo)。在炎癥性疾病環(huán)境下CYPs基本處于低活性狀態(tài)。炎癥因子是炎癥性疾病的共同調(diào)節(jié)因素[8]。目前研究認(rèn)為炎性疾病中CYPs活性下降的機(jī)制可能是由Th1和Th2細(xì)胞分泌的細(xì)胞因子介導(dǎo)的，另外，核受體和microRNA也可能是炎癥過程中下調(diào)CYPs的機(jī)制。

1 Th1細(xì)胞介導(dǎo)的炎癥及其反應(yīng)相關(guān)因子

細(xì)菌、病毒感染引起的炎癥和類風(fēng)濕性關(guān)節(jié)炎屬Th1細(xì)胞主要介導(dǎo)的炎癥反應(yīng)。實驗動物肝外感染革蘭氏陽性菌或革蘭氏陰性菌均可引起參與藥物代謝的1、2和3家族的大部分CYPs酶活性下調(diào)[2,9-11]。革蘭氏陰性細(xì)菌的內(nèi)毒素脂多糖(lipopolysaccharide, LPS)可在人原代肝細(xì)胞培養(yǎng)和小鼠體內(nèi)復(fù)制模型細(xì)菌感染導(dǎo)致的CYPs表達(dá)的降低，并被廣泛應(yīng)用于細(xì)菌感染引起的炎癥反應(yīng)對CYPs的調(diào)控機(jī)制研究中[12-13]。病毒感染同樣引起CYPs表達(dá)的下調(diào)。慢性丙型肝炎病毒感染者代謝CYP3A4探針底物美達(dá)唑侖的能力下降[14]。乙型肝炎病毒感染者肝細(xì)胞中CYP2C19的mRNA表達(dá)下降[15]。肝外病毒感染同樣改變CYPs的活性，例如兒童上呼吸道病毒感染使肝CYP1A2水平降低[6]，HIV患者體內(nèi)肝CYP2E1和CYP2B6的表達(dá)降低[16-17]。此外，Th1主導(dǎo)的非感染性炎癥性疾病類風(fēng)濕性關(guān)節(jié)炎患者體內(nèi)同樣存在CYPs活性下調(diào)，CYP3A4的底物辛伐他汀的代謝清除速率被抑制[3]。

1.1 IL-1β

IL-1β可下調(diào)大鼠和人的CYPs。在大鼠腦損傷模型中，IL-1β下調(diào)CYP2B1和CYP2D1的mRNA以及CYP1A2，CYP2B1，CYP2D1和CYP3A2蛋白質(zhì)的表達(dá)[18]；在人FLC-4肝癌細(xì)胞株中，IL-1β下調(diào)CYP3A4的表達(dá)[19]；在人原代肝細(xì)胞中IL-1β可下調(diào)CYP2C8和CYP3A4的表達(dá)[20]。但采用不同供體的人原代肝細(xì)胞的體外研究發(fā)現(xiàn)，IL-1β對CYPs mRNA 水平的抑制是個體依賴性的，不同個體CYPs的表達(dá)變化對IL-1β的敏感性沒有固定的模式[21]。

1.2 IL-2

除了作為細(xì)胞分泌的促炎細(xì)胞因子參與炎癥反應(yīng)外， IL-2也可用于治療癌癥和HIV等。在體外培養(yǎng)的大鼠原代肝細(xì)胞體系中，IL-2作用后會引起CYP2C11和CYP3A的mRNA和蛋白質(zhì)下調(diào)[22]。對人肝細(xì)胞的研究表明，IL-2誘導(dǎo)其CYP2D6的基因表達(dá), 對CYP2C19和CYP2B6的基因表達(dá)無影響，但卻能夠抑制上述3個酶的活性[23]。在人肝細(xì)胞單獨培養(yǎng)的體系中，與IL-1和IL-6持續(xù)下調(diào)CYPs的作用不同，IL-2可短暫的下調(diào)CYP3A4。而在庫否氏細(xì)胞存在的條件下，IL-2可持續(xù)下調(diào)人肝細(xì)胞內(nèi)的CYP3A[24]。

1.3 IL-6

IL-6是I型炎癥反應(yīng)中分泌的重要的促炎癥分子，可引起廣泛的CYPs抑制。在體外培養(yǎng)的人原代肝細(xì)胞中，IL-6能夠在轉(zhuǎn)錄水平上抑制CYP2E1，CYP3A，CYP1A2，CYP2B6，CYP2C9，CYP2C19，CYP3A4，同時可以不同程度的降低CYP1A2，CYP2B6，CYP2C9，CYP2C19，CYP2D6，CYP3A4的酶活性[20,23]。而且與IL-2不同，該作用并不依賴于庫否氏細(xì)胞即可持續(xù)發(fā)生[24]。而用IL-6受體單克隆抗體tocilizumab能夠恢復(fù)上述IL-6引起的CYP3A4的mRNA表達(dá)的下調(diào)[19]。體內(nèi)實驗也表明IL-6可調(diào)控多種CYPs的表達(dá)，IL-6基因敲除的Engelbreth-Holm-Swarm肉瘤小鼠模型中，midazolam(IL-6拮抗劑)處理后能夠恢復(fù)被抑制的Cyp3a11基因表達(dá)[25]。在小鼠體內(nèi)阻斷IL-6信號傳導(dǎo)會誘導(dǎo)CYP2E1的表達(dá)，進(jìn)而提高乙酰氨基酚的活性代謝產(chǎn)物產(chǎn)生，從而加重肝損傷。在類風(fēng)濕性關(guān)節(jié)炎的病人體內(nèi)，抗IL-6單克隆抗體sirukumab治療后能夠逆轉(zhuǎn)IL-6介導(dǎo)的CYP3A、CYP2C9和CYP2C19的探針底物代謝活性的下降[26]。

1.4 TNF-α

腫瘤壞死因子(tumor necrosis factor，TNF)可促進(jìn)中性粒細(xì)胞吞噬，抗感染，引起發(fā)熱，誘導(dǎo)肝細(xì)胞急性期蛋白合成，促進(jìn)細(xì)胞增殖和分化，是重要的炎癥因子。在體外培養(yǎng)的人原代肝細(xì)胞中，TNF-α處理使CYP1A2、CYP2C、CYP2E1和CYP3A4的mRNA表達(dá)下降，并且能夠不同程度的降低CYP1A2，CYP2C9，CYP2C19，CYP3A4，CYP2B6，CYP2D6的酶活性[23,27]。但在人肝癌細(xì)胞株FLC-4的三維培養(yǎng)模型中，TNF-α能夠抑制CYP3A4的mRNA的表達(dá)，且具有濃度依賴性(0～10 ng·mL-1)和時間依賴性(0～24 h)，卻對CYP3A4的蛋白質(zhì)水平和酶活性的改變無明顯的影響[19]。枸櫞酸桿菌感染的小鼠模型中， Cyp3a11和Cyp3a2的表達(dá)下調(diào)可被TNF-α拮抗劑XPro1595阻斷，表明TNF-α可能是引起Cyp3a11和Cyp3a25表達(dá)下調(diào)的原因[28]。

1.5 IFN-γ

IFN-γ在人肝細(xì)胞和大鼠原代肝細(xì)胞中能夠抑制多種CYP亞型的基因表達(dá)和酶活性[20]。在HepG2細(xì)胞中，IFN-γ能夠抑制胞內(nèi)CYP2E1的啟動子活性從而抑制其表達(dá)。在體外培養(yǎng)的人原代肝細(xì)胞中，IFN-γ能夠在mRNA水平上抑制CYP1A2、2B6的表達(dá)，在轉(zhuǎn)錄后水平上抑制CYP2E1、2B6的表達(dá)，在酶活性上抑制CYP1A2，但是對CYP3A無影響[20,27]。

2 Th2細(xì)胞介導(dǎo)的炎癥及其反應(yīng)相關(guān)因子

寄生蟲感染和過敏性反應(yīng)屬Th2細(xì)胞主要介導(dǎo)的炎癥反應(yīng)，關(guān)于Th2介導(dǎo)的炎癥與CYPs的表達(dá)相關(guān)性的研究相對較少。據(jù)報道瘧原蟲感染導(dǎo)致肝微粒體中CYP2C9，CYP2C19和CYP3A4的酶活性被抑制[29]。對小鼠的研究表明曼氏裂體吸蟲感染慢性期，即蟲卵感染肝臟導(dǎo)致的肝臟發(fā)生基于Th2的炎癥反應(yīng)，使體內(nèi)Cyp1a2，Cyp2c29，Cyp2e1，Cyp2j5，Cyp3a11，Cyp4f13和Cyp4f18的表達(dá)均顯著下調(diào)[30]。然而帶狀泡尾幼蟲感染的大鼠肝CYP1A1，CYP1A2，CYP2B1的活性卻增強[31]。但是非感染性Th2主導(dǎo)的炎癥反應(yīng)中，卵清蛋白誘導(dǎo)的過敏性反應(yīng)引起的炎癥對小鼠肝臟Cyp1a2，Cyp2c29和Cyp3a1表達(dá)均無影響[32]。

關(guān)于Th2分泌的IL-4，IL-5，IL-10，IL-13，TGF-β等細(xì)胞因子對CYPs表達(dá)調(diào)控的研究較少。在小鼠體內(nèi)炎癥模型中，IL-4，IL-10升高的同時肝微粒體中CYP1A和CYP2B的酶活性降低[33]。采用人肝癌細(xì)胞株B16A2 進(jìn)一步研究發(fā)現(xiàn)，該誘導(dǎo)作用是通過STAT6和NFATc1結(jié)合于CYP2E1啟動子的轉(zhuǎn)錄增強所致[34]。在小鼠的重組腺病毒模型中，IL-10顯著升高的同時CYP2J的表達(dá)降低，并且CYP2J也能夠抑制炎癥情況下IL-10的濃度[35]。在曼氏血吸蟲尾蚴感染的血吸蟲病小鼠模型中，肝CYPs活性下降與Th2細(xì)胞分泌的細(xì)胞因子IL-4、IL-5、IL-13的顯著增多存在相關(guān)性[30]。TGF-β能夠在轉(zhuǎn)錄水平上抑制CYP2C8，CYP2C9，CYP2C19和CYP3A4的表達(dá)，對CYP2B6的mRNA有誘導(dǎo)作用，但是在蛋白質(zhì)水平上觀察到CYP2B6蛋白質(zhì)表達(dá)降低[20]。

3 炎癥影響CYPs的其它機(jī)制

核受體與CYPs的表達(dá)調(diào)控密切相關(guān)，參與調(diào)控的核受體包括過氧化物酶體增殖物激活受體(PPARα)，孕烷X受體(PXR)，組成型雄烷受體(CAR)、維甲酸X受體α(RXRα)和法尼醇X受體(FXR)等。在大鼠結(jié)腸炎炎癥過程中，AhR、CAR、PXR、 PPARγ和FXR的 mRNA水平明顯下調(diào)[36]。在潰瘍性結(jié)腸炎的模型小鼠中，Cyp3a11, Cyp1a2, Cyp2c29, Cyp2d9和Cyp2e1的mRNA水平下降，并伴隨著肝臟細(xì)胞因子水平升高和核受體CAR、PXR 的表達(dá)增多[37]。但是關(guān)于這些核受體是否受細(xì)胞因子直接調(diào)控的研究不多。

有文獻(xiàn)報道小分子編碼RNA(microRNA)能在轉(zhuǎn)錄后水平調(diào)控CYPs的表達(dá)。miR-130b、 miR107、 miR103、miR-570和miR-552是目前報道的可下調(diào)CYPs的分子[38]。炎癥是否通過miRNA調(diào)控CYPs表達(dá)研究較少，但有證據(jù)表明這些miRNA可能作為促炎細(xì)胞因子的下游分子，參與調(diào)控CYPs。例如IL-6、 IFN-γ、TNF-α和TGF-β下調(diào)miR107的表達(dá)[39]。

盡管大部分研究認(rèn)為促炎細(xì)胞因子是感染性炎癥疾病中CYPs表達(dá)改變的主要原因，但有研究表明，感染源本身的成分可能也參與了CYPs的表達(dá)調(diào)控。大鼠體內(nèi)研究發(fā)現(xiàn)，在腺病毒感染14天后，炎癥介質(zhì)已經(jīng)消失的情況下，CYP3A2的表達(dá)仍被抑制。該研究認(rèn)為，在促炎細(xì)胞因子消失后，腺病毒分子可能作用于整合素受體分子，進(jìn)而下調(diào)CYP3A2的表達(dá)[7]。此外乙型肝炎病毒X蛋白可能與PXR相互作用，進(jìn)而誘導(dǎo)人肝內(nèi)CYP3A4的酶活性[40]。

在炎癥病理生理條件下，盡管在大部分情況下可觀察到大部分CYPs的mRNA表達(dá)和蛋白質(zhì)受到抑制，但各種不同原因所致的感染或不同個體CYPs的變化情況并不完全一致，這可能是通過細(xì)胞因子、核受體、microRNA和感染源自身分子等多條途徑所致。在體內(nèi)，這一過程與基于藥物代謝酶代謝的藥物清除率的下降有關(guān)，會提高藥物中毒的概率。因此，研究炎癥與CYPs的關(guān)系有助于臨床藥物更合適的使用，避免藥物療效降低甚至引起致命的危險。

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Research progress on the regulation of cytochrome P450 expression in inflammatory diseases

YU Xi1, LI Wei2,3

(1.DepartmentofBasicMedicine,YangzhouUniversitySchoolofMedicine,Yangzhou225001，China; 2.DepartmentofClinicalMedicine,YangzhouUniversitySchoolofMedicine,Yangzhou225001，China; 3.JiangsuKeyLaboratoryofIntegratedTraditionalChineseandWesternMedicineforPreventionandTreatmentofSenileDiseases,Yangzhou225001，China)

CYPs are a class of enzymes in human that mainly catalyze the oxidation reaction of xenobiotic compounds, and responsible for the metabolism of almost 90 percent of clinical drugs. During inflammation, the expression of some members of the CYPs family may be down regulated and the phenotype of drug metabolism may be changed. CYPs induction or inhibition may change the speed of drug metabolism, as a result, affect the concentration of drugs in vivo. The mechanism of the CYPs regulation is probably related to the cytokines, such as IL-1β, IL-2, IL-6, TNF-α, IFN-γ secreted by Th1 cells and IL-4, IL-5, IL-10, IL-13, TGF-β secreted by Th2 cells, as well as nuclear receptors and microRNAs. This article reviews the regulatory role of CYPs in inflammatory diseases and its related mechanisms, which will provide reference for clinical drug use during inflammatory diseases.

cytochrome P450s; inflammation; cytokine; disease; infection

江蘇省高校自然科學(xué)研究面上項目(14KJB310026)；揚州市自然科學(xué)基金青年科技人才項目(YZ2014020)

虞 茜(1991-)，女，碩士研究生。

李 巍，副教授。E-mail: weili@yzu.edu.cn

10.11724/jdmu.2017.01.20

R392.5

A

1671-7295(2017)01-0087-05

虞茜，李巍.炎癥性疾病中細(xì)胞色素P450表達(dá)調(diào)控的研究進(jìn)展[J].大連醫(yī)科大學(xué)學(xué)報，2017,39(1)：87-91.

2016-09-21;

2017-01-01)