馬晶晶 孫沖 張牧焓 耿志明 王道營 徐為民
摘要:4-羥基壬烯醛(HNE)是ω-6 多不飽和脂肪酸(PUFAs)的氧化產(chǎn)物,研究表明HNE具有生理和病理學(xué)作用,與多種疾病的發(fā)生、發(fā)展密切相關(guān)。就HNE的形成機(jī)制、形態(tài)分布、代謝、病理和生理學(xué)意義、檢測方法、安全問題等進(jìn)行綜述,并對提升食品營養(yǎng)風(fēng)味、減少HNE形成的新型食品加工方法進(jìn)行展望。
關(guān)鍵詞:4-羥基壬烯醛;ω-6 多不飽和脂肪酸;氧化;HNE形成機(jī)制;病理學(xué)意義;生理學(xué)意義;HNE檢測
中圖分類號: TS201.6文獻(xiàn)標(biāo)志碼: A文章編號:1002-1302(2021)19-0057-07
生物膜磷脂的多不飽和脂肪酸(PUFAs)在酶、自由基等作用下,發(fā)生過氧化反應(yīng),產(chǎn)生一系列復(fù)雜產(chǎn)物,如氫過氧化物、醇、酮、醛等[1]。內(nèi)源性4-羥基壬烯醛(HNE)來源于生物體內(nèi)ω-6 PUFAs的氧化,是體內(nèi)脂質(zhì)氧化最具代表性的醛類產(chǎn)物[2]?,F(xiàn)有研究表明,HNE具有降低或抑制酶活、修飾蛋白質(zhì)結(jié)構(gòu)、干擾細(xì)胞正常功能、損傷細(xì)胞組分等作用[3];內(nèi)源性HNE與多種疾病的發(fā)生、發(fā)展密切相關(guān),如炎癥、動脈粥樣硬化、缺血再灌注損傷、帕金森綜合癥和阿爾茲海默病等[4]。因此,HNE相關(guān)研究一直是病理和生理學(xué)研究的熱點。
除了內(nèi)源性HNE,外源性HNE也廣泛存在于富含油脂的食品中[5]。研究表明,通過食物攝取進(jìn)入體內(nèi)的HNE,能夠發(fā)揮內(nèi)源性HNE同等的生理作用[6]。近年來,隨著食品中HNE的發(fā)現(xiàn),其形成機(jī)制、形態(tài)分布及潛在的安全危害也引起了人們廣泛關(guān)注。本文就HNE的形成機(jī)制、形態(tài)分布、代謝、病理和生理學(xué)意義、檢測方法等進(jìn)行簡要綜述,并對食品中HNE的相關(guān)研究作一些展望。
1HNE的形成機(jī)制
自發(fā)現(xiàn)以來,科研工作者陸續(xù)提出HNE的多種形成機(jī)制和途徑。研究表明,HNE是ω-6 PUFAs的氧化產(chǎn)物,ω-6 PUFAs首先氧化形成氫過氧化物,然后再進(jìn)一步降解產(chǎn)生HNE[7-8]。
亞油酸(LA)是哺乳動物體內(nèi)含量最多、也是HNE相關(guān)研究中最常用的ω-6 PUFA,本文選擇LA來闡述HNE的形成機(jī)制。LA氧化形成HNE主要分為兩大步驟:第1步,LA轉(zhuǎn)變?yōu)闅溥^氧化十八碳二烯酸(HPODEs);第2步,HPODEs降解形成HNE。
第1步,LA轉(zhuǎn)化為HPODEs,可以借助酶促或自由基誘導(dǎo)的方式,HPODEs主要包括9-HPODE和13-HPODE這2種異構(gòu)體(圖1)。研究表明,大豆脂氧酶可以選擇性地促進(jìn)LA生成13-HPODE,而番茄脂氧酶作用時主要得到9-HPODE[9];自由基誘導(dǎo)氧化條件下,2種異構(gòu)體生成的比例接近 1 ∶1[10]。第2步,HPODEs降解形成HNE,主要以自由基誘導(dǎo)為主,9-HPODE和13-HPODE這2種異構(gòu)體在自由基誘導(dǎo)體系下降解形成HNE的機(jī)制并不相同,9-HPODE有2種途徑形成HNE(圖2):一種是9-HPODE發(fā)生氫氧均裂,得到的過氧自由基進(jìn)攻鄰位的碳碳雙鍵,形成9,10-二氧環(huán)丁烷自由基,該自由基結(jié)合一分子氧后,裂解形成4-過氧化壬烯醛(HPNE),HPNE是HNE的前體物質(zhì),在適宜的還原體系中,可轉(zhuǎn)變?yōu)镠NE[11];另一種是在酸性條件下,經(jīng)Hock重排,裂解形成相應(yīng)中間體3Z-壬烯醛(3Z-NA),3Z-NA可經(jīng)氧化、還原形成HNE[12]。與9-HPODE相比,13-HPODE降解形成HNE的途徑要復(fù)雜一些,可分為4種途徑(圖3):第1種是13-HPODE的8號碳結(jié)合一分子氧,轉(zhuǎn)變?yōu)?,13-DHPODE,經(jīng)Hock重排得到5-過氧化癸二烯醇,該化合物的烯醇端碳碳雙鍵經(jīng)氧化斷裂,可得到相應(yīng)的甲酸和HPNE,HPNE可進(jìn)一步轉(zhuǎn)化為HNE[13];第2種是13-HPODE的10號碳受到氧進(jìn)攻,轉(zhuǎn)變?yōu)?0,13-DHPODE,該中間體經(jīng)Hock重排、裂解形成HPNE,再還原得到HNE[14];第3種是在形成10,13-DHPODE的基礎(chǔ)上,繼續(xù)結(jié)合一分子烷氧自由基,形成相應(yīng)的二聚體,在二價鐵離子的作用下,經(jīng)β裂解、還原形成HNE[15];第4種是13-HPODE形成環(huán)氧中間體,在金屬離子及氧氣作用下,形成不對稱的二環(huán)氧碳酰自由基,碳碳鍵斷裂后,形成相應(yīng)的產(chǎn)物4-羰基-2-壬烯醛(ONE)和HNE[16]。除了自由基途徑,在植物脂氧酶(9-LOX)和過氧化氫裂解酶的共同作用下,LA也能夠通過酶促途徑降解形成HNE[15]。
HNE的形成受諸多因素干擾,形成過程復(fù)雜,是否還存在其他形成途徑還有待進(jìn)一步探究。
2HNE的形態(tài)分布
HNE分子結(jié)構(gòu)中含有3種官能團(tuán),即醛基、碳碳雙鍵和羥基,其化學(xué)性質(zhì)活潑,除了游離形態(tài)外,HNE還能與多種其他化合物作用,形成結(jié)合形態(tài)。
蛋白質(zhì)是HNE作用的主要對象,邁克爾(Michael)加成反應(yīng)和形成席夫(Schiff)堿是HNE和蛋白質(zhì)結(jié)合的2種主要方式。HNE與蛋白質(zhì)上多種氨基酸(包括半胱氨酸、組氨酸、賴氨酸、精氨酸等)殘基的側(cè)鏈結(jié)合,以改變蛋白質(zhì)的結(jié)構(gòu)和功能[17]。Xu等報道了HNE通過和蛋白質(zhì)上的賴氨酸結(jié)合,形成具有熒光性的共價偶聯(lián)產(chǎn)物[18]。2001年,Gardner等報道了HNE與血凝素樣氧化低密度脂蛋白受體-1(LOX-1)側(cè)鏈上的組氨酸形成Michael加成產(chǎn)物,屏蔽了鐵離子結(jié)合位點,從而降低酶活[19]。
作為巰基化合物的代表,谷胱甘肽(GSH)是細(xì)胞內(nèi)一種重要的水溶活性物質(zhì)。在生理條件下,HNE能夠和GSH形成復(fù)合物,加劇氧化應(yīng)激的程度[20]。
磷脂是細(xì)胞膜的重要組成部分,也能夠和HNE結(jié)合,磷脂酰乙醇胺、磷脂酰絲氨酸等分子中含有活潑的伯胺基團(tuán),通過Michael加成反應(yīng)或形成Schiff堿的方式與HNE結(jié)合[21]。
HNE和核酸類物質(zhì)形成復(fù)合物,干擾DNA復(fù)制、RNA轉(zhuǎn)錄,對細(xì)胞產(chǎn)生基因毒性[22-23]。DNA中的鳥嘌呤是HNE攻擊的主要對象,Chen等分別報道了HNE和鳥嘌呤的結(jié)合方式及形成的相應(yīng)產(chǎn)物[24-25]。
除了這些結(jié)合形態(tài),HNE還能與內(nèi)源性的多肽結(jié)合,如含組氨酸的肽段、胰島素、血管緊張素等[26-29]。此外,HNE 還能與一些小分子結(jié)合,如輔助因子、維他命、H2S等[30-32]。
3HNE的代謝
健康人體內(nèi)HNE能夠維持一定的水平,離不開代謝作用。體內(nèi)HNE的代謝可以分為第Ⅰ相代謝和第Ⅱ相代謝2種方式,前者主要借助氧化還原酶將HNE轉(zhuǎn)化為無毒化合物,后者主要通過與GSH結(jié)合來清除HNE。
3.1第Ⅰ相代謝
第Ⅰ相代謝主要包含氧化和還原2種途徑。HNE氧化代謝途徑主要通過醛脫氫酶(ALDH)來實現(xiàn),該酶是緩解及預(yù)防產(chǎn)生細(xì)胞毒性的一類酶,能夠選擇性地將HNE分子中的醛基轉(zhuǎn)化為羧基,形成無活性的烯酸(HNA)[33]。HNA經(jīng)β氧化,可轉(zhuǎn)變?yōu)镃O2和H2O[34];在細(xì)胞色素P450(CYP450)的作用下,經(jīng)ω氧化進(jìn)一步轉(zhuǎn)化為二醇和三醇,端位的醇羥基可繼續(xù)氧化為相應(yīng)的羧酸[35]。乙醇脫氫酶(ADH)、醛酮/還原酶(AKR)以及烯醛/烯酮氧化還原酶(AOR)是HNE還原代謝常用的酶。ADH和AKR能夠選擇性地將醛基還原成醇羥基,形成無活性的二醇產(chǎn)物(DHN)[36]。而AOR是一類具有還原碳碳雙鍵能力的酶。近期的研究表明,AOR過度表達(dá),可以將體內(nèi)堆積的HNE轉(zhuǎn)化4-羥基壬醛(HN),從而保護(hù)細(xì)胞免受HNE的侵害[37]。
3.2第Ⅱ相代謝
第Ⅱ相代謝主要由HNE和GSH形成無活性大分子(GS-HNE)來完成,在谷胱甘肽轉(zhuǎn)移酶(GSTs)、羰基還原酶(CBR1)等催化下,GSH與HNE通過Michael加成反應(yīng),保留的醛基可以繼續(xù)與分子內(nèi)的巰基形成環(huán)化產(chǎn)物,所得環(huán)化產(chǎn)物和直接加成產(chǎn)物的比例接近于1 ∶1[3]。在氧化或還原酶作用下,GS-HNE可進(jìn)一步形成GS-HNA、GS-ONA、GS-DHN等化合物[38-40]。在γ谷氨酸轉(zhuǎn)移酶以及胱氨酸S-聚合-N-乙酰轉(zhuǎn)移酶的作用下,GS-HNE、GS-DHN、GS-HNA等的GS端可進(jìn)一步水解、?;?,轉(zhuǎn)變?yōu)榱虼寄蛩幔∕A),形成的 HNE-MA、HNA-MA和DHN-MA可直接排出體外[41]。
4HNE的病理和生理學(xué)意義
健康人體血漿中HNE的平均含量約為 11.62? μg/L[42],體內(nèi)HNE的濃度與細(xì)胞種類及代謝環(huán)境等因素有關(guān),胞內(nèi)HNE的濃度對細(xì)胞有明顯影響。圖4展示了HNE濃度由較低的生理水平逐漸升高后,細(xì)胞內(nèi)的生化過程及狀態(tài)變化:生理水平HNE在各種酶作用下,被完全代謝,不影響細(xì)胞的存活;低濃度HNE能夠發(fā)揮重要的信號傳導(dǎo)作用,如刺激基因表達(dá)、促進(jìn)抗氧化能力、提高應(yīng)激能力等;中等水平的HNE,能夠發(fā)出蛋白質(zhì)受損信號,影響蛋白質(zhì)和細(xì)胞器正常功能,引發(fā)自噬、衰老及細(xì)胞周期停滯;高濃度和極高濃度的HNE,能夠繼續(xù)和蛋白質(zhì)、DNA等形成復(fù)合物,引發(fā)細(xì)胞毒性和基因毒性,產(chǎn)生病理作用,引發(fā)細(xì)胞程序性凋亡[43]。
氧化應(yīng)激和不斷積累的脂質(zhì)過氧化是多種疾病發(fā)病和病變的重要影響因素,HNE作為活潑的脂質(zhì)氧化標(biāo)志物,在地中海貧血、瘧疾、維生素E缺乏、B16黑色素瘤、低血容量性休克和創(chuàng)傷患者的相關(guān)組織中均能檢測到[44-49]。此外,HNE與心臟疾病、癌癥、神經(jīng)退行性疾病等的發(fā)生、發(fā)展密切相關(guān)。研究表明,擴(kuò)張型心肌病患者體內(nèi)HNE修飾蛋白的表達(dá)量比健康人群高5倍[50]。除了心臟疾病,HNE對癌癥發(fā)生及發(fā)展有重要的影響。HNE不僅能夠修飾DNA的結(jié)構(gòu),還能夠干預(yù)DNA的修復(fù)機(jī)制,導(dǎo)致DNA受損,促進(jìn)癌癥的形成[51]。神經(jīng)系統(tǒng)含有豐富的ω-6 PUFAs、金屬離子,參與頻繁的氧化還原轉(zhuǎn)換,是形成HNE的重要場所。帕金森綜合征是第二大神經(jīng)退行性疾病,HNE不僅能夠修飾大腦路易斯體中α-突觸核蛋白的結(jié)構(gòu),誘導(dǎo)該蛋白
發(fā)生降解、聚集,還能夠作用于多巴胺轉(zhuǎn)運(yùn)器,抑制多巴胺吸收,降低體內(nèi)多巴胺水平,這二者均能加重帕金森綜合征病情[52-53]。阿爾茨海默病是研究最為廣泛的神經(jīng)退行性紊亂病,研究表明患者體內(nèi)的HNE水平顯著高于健康人群,HNE通過修飾β-淀粉樣蛋白結(jié)構(gòu)、促進(jìn)自由基形成,加劇該病的發(fā)展[54-55]。
5HNE的檢測方法
HNE具有的病理生理學(xué)作用引起了研究人員廣泛關(guān)注,體內(nèi)HNE水平被認(rèn)為是脂質(zhì)代謝最重要的指標(biāo)之一。HNE本身容易揮發(fā)、分解,當(dāng)pH值>9或pH值<1,或者溫度高于50 ℃時,HNE容易分解;HNE在氮?dú)獯祾?、真空濃縮等過程中也容易揮發(fā),這給HNE的提取工作帶來了極大挑戰(zhàn)。此外,HNE具有紫外、熒光檢測響應(yīng)低,質(zhì)譜離子化效率不高等特性,須借助衍生試劑來提高檢測靈敏度。目前,按照HNE的形態(tài),檢測方法可以分為游離形態(tài)和結(jié)合形檢測方法。
5.1游離形態(tài)HNE的檢測方法
光譜分析法和質(zhì)譜法是游離形態(tài)HNE常用的檢測方法。這2種方法常借助衍生試劑來完成,因此衍生試劑的選擇是一個關(guān)鍵因素,應(yīng)滿足衍生速度快、衍生產(chǎn)物穩(wěn)定、容易分離和檢測等要求。光譜法常用的衍生試劑有肼和酮類。2,4-二硝基苯肼是最常用的肼類衍生試劑,它能與HNE結(jié)合形成穩(wěn)定的苯腙,該衍生產(chǎn)物具有良好的紫外吸收能力,可以通過高效液相-紫外檢測器(HPLC-UV)進(jìn)行檢測分析,適用于油脂、肉品、水產(chǎn)、蔬菜等樣本[56]。1,3-環(huán)己二酮是酮類常用的衍生試劑,在銨鹽的作用下,它與HNE作用形成的產(chǎn)物具有熒光性,可通過高效液相-熒光檢測器(HPLC-FLD)來進(jìn)行定量分析[57]。質(zhì)譜技術(shù)的成熟,使得HNE的分析更加精準(zhǔn),通過質(zhì)荷比的特異性,可對相應(yīng)物質(zhì)進(jìn)行定性定量分析。氣相色譜-質(zhì)譜聯(lián)用(GC-MS)技術(shù)是HNE常用的檢測手段,羥胺類衍生試劑與HNE經(jīng)醛胺縮合、羥基衍生操作后,形成的產(chǎn)物適合采用GC-MS技術(shù)分析[58]。近年來,食品中HNE的分析方法取得了較多關(guān)注,植物油脂富含不飽和脂肪酸,是HNE形成的重要來源,Globisch等采用兩步衍生法,先將HNE轉(zhuǎn)化為穩(wěn)定的肟醚,再對羥基進(jìn)行硅烷基化,采用GC-MS法對多種植物油的HNE進(jìn)行普查[59-60]。苯肼類衍生結(jié)合液相色譜串聯(lián)質(zhì)譜(LC-MS/MS)技術(shù)也是食品中HNE常用的檢測方法,適應(yīng)于多種油脂、油炸食品中HNE含量的分析[61-64]。最近,筆者所在課題組就肉制品中HNE的提取及分析方法進(jìn)行研究,開發(fā)了液氮速凍制樣、同位素內(nèi)標(biāo)添加、低溫液提取的方法,提升了肉制品中HNE分析方法的靈敏度和精密度[65]。盡管游離形態(tài)HNE的分析技術(shù)研究取得了一定的進(jìn)展,但仍存在一些問題:(1)游離態(tài)HNE提取方法不完善,提取過程中難以控制HNE的形成、轉(zhuǎn)化以及分解;(2)樣品重復(fù)性差,回收率不高。
5.2結(jié)合形態(tài)HNE的檢測方法
與游離形態(tài)HNE檢測相比,結(jié)合形態(tài)HNE的檢測情況相對復(fù)雜一些,不僅需要找出HNE結(jié)合形態(tài)的形成部位、種類、結(jié)合方式等相關(guān)信息,還需建立合適的檢測方法。免疫組織化學(xué)和免疫細(xì)胞化學(xué)是結(jié)合形態(tài)HNE檢測早期的使用方法,可將免疫反應(yīng)的特異性和組織化學(xué)的可見性巧妙結(jié)合,促進(jìn)了部分結(jié)合形態(tài)HNE的定位、定性以及定量分析,如檢測低密度脂蛋白上HNE-賴氨酸的水平、血清中HNE-多聚氨基酸的結(jié)合種類和數(shù)量、細(xì)胞裂解產(chǎn)物中HNE-組氨酸的含量以及尿液中DHN-HNE的含量等。盡管這些技術(shù)證實了HNE能以結(jié)合態(tài)的方式存在,但存在抗體制備專一性不強(qiáng)、交叉反應(yīng)率高等問題。肽段質(zhì)量指紋圖譜、質(zhì)譜序列、中性掃描損失等是質(zhì)譜常用的分析手段,用來解析HNE修飾蛋白、肽段等的種類和結(jié)合位點,這些檢測有效促進(jìn)了結(jié)合形態(tài)HNE的分析工作,但由于結(jié)合形態(tài)HNE的豐度不高,許多工作仍集中在富集方法、HNE修飾種類、結(jié)合位點等方面,結(jié)合形態(tài)HNE的分析工作仍處于起步階段,面臨的困難和需要解決的問題還有很多[14]。
6食品中HNE的安全問題
不論是新鮮食材,還是貯藏、加工等過程中的食品,脂質(zhì)氧化都不可避免。人體內(nèi)的HNE包括內(nèi)源性和外源性2種:內(nèi)源性的HNE由細(xì)胞或組織中ω-6 PUFAs分解代謝產(chǎn)生;外源性的HNE主要通過膳食攝入。通過膳食獲取的HNE含量與食品中HNE含量緊密相關(guān),食品的種類、貯藏加工方式均會影響HNE的形成,研究人員對各類食品中的游離形態(tài)HNE含量進(jìn)行了調(diào)查分析,發(fā)現(xiàn)油脂、油炸土豆及肉制品中富含HNE,過多地攝取這些食物可能會影響人類的健康[66]。此外,HNE性質(zhì)比較活潑,能夠與多種大分子活性物質(zhì)形成復(fù)合物,在一定條件下,這些結(jié)合態(tài)的復(fù)合物與游離形態(tài)的HNE可互相轉(zhuǎn)化,已有研究報道尚不能提供完整、可靠的HNE含量、形態(tài)等信息,但從中可以看出,富含不飽和脂肪酸的食物普遍存在HNE。由于結(jié)合形態(tài)HNE的存在,真實HNE的含量可能遠(yuǎn)遠(yuǎn)超過檢測水平。
值得注意的是,除了膳食本身攜帶的HNE,膳食中HNE的前體物質(zhì)進(jìn)入消化器官后,能夠繼續(xù)形成HNE,提高體內(nèi)HNE水平,并可能發(fā)揮內(nèi)源性HNE相同的病理生理學(xué)作用[67-69]。迄今為止,人體內(nèi)HNE水平與多種疾病相關(guān)性的研究均未能有效區(qū)分體內(nèi)HNE的來源,因此食品中普遍含有的HNE對人體健康具有潛在的安全風(fēng)險。食品中HNE的安全隱患不容忽視,食品尤其是肉制品中HNE的形態(tài)鑒定與分布、分析技術(shù)、形成規(guī)律及機(jī)制、暴露風(fēng)險評價等值得開展進(jìn)一步研究。
7研究展望
HNE是脂質(zhì)氧化過程中ω-6 PUFAs的氧化產(chǎn)物。盡管在生理和病理學(xué)領(lǐng)域的研究取得了重大進(jìn)展,但在食品領(lǐng)域的研究尚處于起步狀態(tài)。HNE在食品貯藏及加工過程中的形成機(jī)制、形態(tài)分布及演變情況、定量分析方法、風(fēng)險評估等將受到越來越多的關(guān)注。目前食品中減少HNE形成的方法主要包括采用多酚類阻斷HNE形成、把控食物原料、控制食品加工方法等,希望開發(fā)更多的方法在提升食品營養(yǎng)價值、風(fēng)味的同時,又能抑制HNE的形成。
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基金項目:國家自然科學(xué)基金(編號:31901716、31671877);國家現(xiàn)代農(nóng)業(yè)(肉雞)產(chǎn)業(yè)體系建設(shè)專項(編號:CARS-41);江蘇省自然科學(xué)基金(編號:BK20171324);江蘇省科技計劃(編號:XZ-SZ2019)。
作者簡介:馬晶晶(1988—),女,安徽銅陵人,博士,助理研究員,研究方向為肉品安全與質(zhì)量控制。E-mail:jingjingma2017@163.com。
通信作者:耿志明,碩士,研究員,研究方向為肉品安全與質(zhì)量控制。E-mail:zmgeng@163.com。