張京紅 盧 健 陳彩珍 劉承宜

摘要:有氧代謝不可避免地產(chǎn)生活性氧(reactive oxygen species,ROS)。盡管過(guò)多的ROS具有毒性作用,但一定的ROS卻在細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)和抗氧化酶基因表達(dá)上起著重要的作用。運(yùn)動(dòng)訓(xùn)練能建立和維持氧化-抗氧化內(nèi)穩(wěn)態(tài)(oxidant-antioxidant homeostasis,OAH)。OAH可以將ROS維持在一定的水平。OAH可以抵抗的ROS漲落有一定的范圍(OAH-specific ROS level zone,oROZ),其最大值和最小值分別記為maxROZ和minROZ。將剛能引起氧化應(yīng)激的ROS稱為應(yīng)激ROS水平(stressful ROS level,sROS)。如果ROS水平經(jīng)常低于minROZ,OAH就會(huì)退化。當(dāng)ROS水平超過(guò)maxROZ達(dá)到sROS時(shí),就可以打破現(xiàn)有OAH,建立抗氧化能力更強(qiáng)的新OAH。如果ROS水平引起細(xì)胞凋亡或損傷,補(bǔ)充外源性抗氧化劑是有益的。如果將ROS水平降低到minROZ之下,就會(huì)影響OAH的維持,外源性抗氧化劑的補(bǔ)充是有害的。如果將sROS降低到oROZ之中,就會(huì)影響新的OAH的建立,外源性抗氧化劑的補(bǔ)充是無(wú)益的。

關(guān)鍵詞:運(yùn)動(dòng)生物化學(xué);活性氧;抗氧化劑;氧化應(yīng)激;內(nèi)穩(wěn)態(tài);綜述

中圖分類(lèi)號(hào):G804.2文獻(xiàn)標(biāo)識(shí)碼:A文章編號(hào):1006-7116(2009)11-0100-05

Review of researches on active oxygen and antioxidant supplementation during exercising from the perspective of homeostasis

ZHANG Jing-hong1,LU Jian1,CHEN Cai-zhen1,LIU Cheng-yi2

(1.School of Physical Education & Health,East China Normal University,Shanghai 200241,China;

2.Laboratory of Laser Sports Medicine,South China Normal University,Guangzhou 510006,China)

Abstract: It is inevitable for aerobic metabolism to produce active oxygen (OA). Although excessive OA is toxic, a certain level of OA plays an important role in cell signal transduction and antioxidase gene expression. Sports training can establish and maintain a homeostasis between oxidation and antioxidation (HO-A), which can maintain OA to a certain level. There is a certain range (RH) in which the HO-A is able to resist the fluctuation of the OA level. The maximum value and minimum value of RH are denoted as maxRH and minRH respectively. The OA level that is just high enough to cause an oxidation reaction is called the reactive active oxygen (ROA) level. If the OA level is frequently lower than the minRH, the HO-A will degenerate. When the OA level exceeds the maxRH to reach the ROA level, the existing HO-A can be broken, and a more powerful new HO-A will be established. If the OA level causes the decease or damage of cells, supplementing an exogenous antioxidant is helpful. If the OA level is lowered to a level below the minRH, the maintenance of the HO-A will be affected, and the supplementation of an exogenous antioxidant is harmful. If the ROA level is lowered to a level within the RH, the establishment of a new HO-A will be affected, and the supplementation of an exogenous antioxidant is useless.

Key words: sports biochemistry;active oxygen;antioxidant;oxidative reaction;homeostasis;overview

關(guān)于抗氧化劑的補(bǔ)充存在著較大的爭(zhēng)議[1]。面對(duì)激烈的競(jìng)技體育發(fā)展趨勢(shì),如何提高運(yùn)動(dòng)員的抗氧化能力,減少氧化損傷的發(fā)生,一直是世界各國(guó)運(yùn)動(dòng)醫(yī)學(xué)界面臨的一個(gè)難題,有關(guān)的基礎(chǔ)與臨床研究也在不斷地深入開(kāi)展。對(duì)于這一情況,如果我們能正確地審視運(yùn)動(dòng)中活性氧(reactive oxygen species,ROS)的水平及作用,那么對(duì)抗氧化劑補(bǔ)充的問(wèn)題就會(huì)有一個(gè)較為清晰的認(rèn)識(shí)。本文從內(nèi)穩(wěn)態(tài)的角度評(píng)述了運(yùn)動(dòng)中ROS與抗氧化劑補(bǔ)充的問(wèn)題。

1運(yùn)動(dòng)訓(xùn)練與ROS水平

有氧代謝時(shí)線粒體能量轉(zhuǎn)換不可避免的導(dǎo)致ROS生成甚至發(fā)生氧化應(yīng)激。線粒體呼吸鏈電子漏是運(yùn)動(dòng)性內(nèi)源ROS的主要源頭,運(yùn)動(dòng)強(qiáng)度越大ROS的生成也越多[2-3]。劉承宜等人[4]從內(nèi)穩(wěn)態(tài)的角度將運(yùn)動(dòng)訓(xùn)練分為超常訓(xùn)練(extraordinary training,ET)和常規(guī)訓(xùn)練(ordinary training,OT)兩類(lèi)。ET階段ROS變化較大,生成較多,而OT階段ROS生成較穩(wěn)定[5]。

運(yùn)動(dòng)增加了ROS的生成,但也促進(jìn)了抗氧化酶的表達(dá),ROS由氧化-抗氧化的內(nèi)穩(wěn)態(tài)(oxidant -antioxidant homeostasis,OAH)[6-7]維持在一定的水平。為了討論方便,將OAH所維持的ROS水平稱為OAH特異的ROS水平(OAH-specific ROS level,oROS)。OAH可以抵抗的ROS漲落有一定的范圍(OAH-specific ROS level zone,oROZ),其最大值和最小值分別記為maxROZ和minROZ。ROS水平超過(guò)oROZ就可以引起氧化應(yīng)激。低水平氧化應(yīng)激(low level oxidative stress,LOS)可以調(diào)節(jié)細(xì)胞的功能,屬于有益的應(yīng)激[8],相應(yīng)的ROS稱為應(yīng)激ROS水平(stressful ROS level,sROS)。高水平氧化應(yīng)激(high level oxidative stress,HOS)引起細(xì)胞凋亡甚至損傷細(xì)胞,屬于有害的應(yīng)激[8]。由于個(gè)體差異,不同個(gè)體的各種ROS的水平是不同的。

2運(yùn)動(dòng)引起ROS的適應(yīng)機(jī)制

不可否認(rèn)運(yùn)動(dòng)中生成過(guò)量的ROS可導(dǎo)致代謝和心血管等方面的相關(guān)疾病,但最近人們開(kāi)始關(guān)注ROS的信號(hào)轉(zhuǎn)導(dǎo)作用[9]。細(xì)胞內(nèi)生成的ROS可能不是一種“副產(chǎn)品”,而是“目的性”的產(chǎn)物。ROS的角色是細(xì)胞內(nèi)一類(lèi)重要的信號(hào)分子[10],在細(xì)胞內(nèi)穩(wěn)態(tài)調(diào)節(jié)等細(xì)胞生命活動(dòng)中作為第二信使參與多種因子細(xì)胞生物學(xué)效應(yīng)的啟動(dòng)[11-12]。一般當(dāng)ROS水平達(dá)到minROZ就可激活信號(hào)通路,引起體內(nèi)抗氧化酶的表達(dá)[13]。當(dāng)ROS水平超過(guò)maxROZ達(dá)到sROS 時(shí),就可打破現(xiàn)有OAH,通過(guò)上調(diào)抗氧化酶的表達(dá)來(lái)建立抗氧化能力更強(qiáng)的OAH[6]。一旦ROS達(dá)到HOS水平就會(huì)導(dǎo)致細(xì)胞凋亡或氧化損傷。如果ROS水平經(jīng)常低于minROZ,抗氧化酶表達(dá)失活,OAH就會(huì)退化,相當(dāng)于運(yùn)動(dòng)員停訓(xùn)引起運(yùn)動(dòng)水平降低或丟失[14]。

OAH的品質(zhì)由oROS的高低和穩(wěn)定程度來(lái)表征。oROS越低,越穩(wěn)定,OAH的品質(zhì)越高。運(yùn)動(dòng)訓(xùn)練是提高OAH品質(zhì)的方法之一[4]。ET通過(guò)產(chǎn)生LOS打破現(xiàn)有OAH,從而上調(diào)抗氧化酶表達(dá)建立新的品質(zhì)更高的OAH[15];OT則維持新建立的OAH。這是提高機(jī)體抗氧化能力的一個(gè)重要方法。Finkel等人[16]提出提高機(jī)體內(nèi)源性抗氧化能力的最好方法可能就是氧化應(yīng)激本身。Ji[17]論述了通過(guò)對(duì)氧化還原敏感的信號(hào)轉(zhuǎn)導(dǎo)通路的激活,運(yùn)動(dòng)誘導(dǎo)的氧化應(yīng)激作為一種重要的信號(hào)分子來(lái)刺激骨骼肌抗氧化系統(tǒng)對(duì)應(yīng)激的適應(yīng)。當(dāng)然,運(yùn)動(dòng)中所產(chǎn)生的ROS水平不能太高,否則將引起細(xì)胞凋亡或造成氧化損傷,對(duì)機(jī)體的健康和運(yùn)動(dòng)成績(jī)不利[18]。

在ROS激活引起抗氧化酶表達(dá)上調(diào)的信號(hào)轉(zhuǎn)導(dǎo)通路中,促分裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路和核轉(zhuǎn)錄因子κB(nuclear factor-κB,NF-κB)通路是細(xì)胞處理氧化應(yīng)激最為關(guān)鍵的兩條通路[6,15]。在MAPK通路上,升高的ROS激活RAS、Rac1和RhoA等,并進(jìn)一步激活下游蛋白激酶,如Raf-1、MEKK1-3和MEKK4等,信號(hào)繼續(xù)下傳,直至激活ERK、P38和JNK,繼而激活A(yù)P-1等轉(zhuǎn)錄因子,引起抗氧化酶表達(dá)上調(diào)[19]。在NF-κB通路上,運(yùn)動(dòng)引起ROS升高,ROS激活酪氨酸蛋白激酶使IκBα Tyr位點(diǎn)磷酸化進(jìn)而活化游離并移入核內(nèi)的NF-κB[20]。運(yùn)動(dòng)是一個(gè)復(fù)雜的過(guò)程,運(yùn)動(dòng)中產(chǎn)生的ROS可引起復(fù)雜的信號(hào)轉(zhuǎn)導(dǎo),而通過(guò)這些轉(zhuǎn)導(dǎo)可提高人體的抗氧化能力[6,17]。

3運(yùn)動(dòng)與抗氧化劑的補(bǔ)充

3.1抗氧化劑補(bǔ)充的益處

不同階段補(bǔ)充抗氧化劑的影響是不同的?？寡趸瘎┭a(bǔ)充是否有益取決于體內(nèi)ROS的水平[21]。內(nèi)源性抗氧化酶的表達(dá)可能具有滯后性[22]。機(jī)體無(wú)法應(yīng)付HOS,需要補(bǔ)充外源性抗氧化劑來(lái)降低ROS水平。一系列研究也報(bào)道了運(yùn)動(dòng)中補(bǔ)充抗氧化劑帶來(lái)的益處。早期的一些文獻(xiàn)就報(bào)道了補(bǔ)充抗氧化維生素可減輕人體的氧化損傷[23-24]。Fang等人[25]的研究表明維生素C(vitamine C,VC)和維生素E(vitamine E,VE)的補(bǔ)充有助于提高體內(nèi)抗氧化酶的活性。Claudio等人[26]對(duì)賽前訓(xùn)練期間的5名優(yōu)秀足球運(yùn)動(dòng)員給予VC和VE補(bǔ)充,發(fā)現(xiàn)補(bǔ)充抗氧化劑降低了脂質(zhì)過(guò)氧化和肌肉損傷水平,但沒(méi)有提高受試者的運(yùn)動(dòng)成績(jī)。同樣Kon等人[3]對(duì)18名日本優(yōu)秀劍道運(yùn)動(dòng)員進(jìn)行隨機(jī)雙盲試驗(yàn),其中10名補(bǔ)充輔酶Q10(300 mg/d,持續(xù)20 d),另外8名給予同等劑量的安慰劑,發(fā)現(xiàn)給予輔酶Q10組的肌酸激酶和脂質(zhì)過(guò)氧化物水平均比安慰劑組低。Kerksick等人[27]報(bào)道了補(bǔ)充抗氧化劑可降低HOS,提高機(jī)體的健康和運(yùn)動(dòng)成績(jī)。Sureda等人[28]通過(guò)隨機(jī)雙盲試驗(yàn),對(duì)14名參加半程馬拉松的業(yè)余運(yùn)動(dòng)員給予VC與VE混合物(分別為152 mg/d、50 mg/d)或安慰劑,為期1個(gè)月。他們發(fā)現(xiàn),劇烈運(yùn)動(dòng)使安慰劑組發(fā)生了脂質(zhì)過(guò)氧化,抗細(xì)胞凋亡因子-2表達(dá)下降,而抗氧化劑組運(yùn)動(dòng)誘導(dǎo)的氧化損傷較低,且沒(méi)有影響細(xì)胞對(duì)運(yùn)動(dòng)的適應(yīng)。Jana等人[29]對(duì)48只Wistar雄性大鼠隨機(jī)分成4組,其中一組運(yùn)動(dòng)且給予亞硒酸鈉(6 mg/kg)混合硫酸鋅(3 mg/kg),10周后發(fā)現(xiàn)運(yùn)動(dòng)而不給予抗氧化劑組的生殖系統(tǒng)發(fā)生了氧化損傷,而給予亞硒酸鈉與硫酸鋅混合組卻得到了保護(hù)。最近,Mara?ón等人[30]采用對(duì)照試驗(yàn)對(duì)參加跳躍比賽的24匹馬中的8匹給予甲基磺胺甲烷(methyl sulphonyl methane,MSM)(8 mg/kg),另外8匹給予MSM(8 mg/kg)混合VC(5 mg/kg),發(fā)現(xiàn)不給予抗氧化劑組發(fā)生了脂質(zhì)過(guò)氧化,抗氧化酶的活性下降,給予MSM組未發(fā)生上述變化,而給予MSM混合VC組的各項(xiàng)指標(biāo)均較佳。

針對(duì)上述補(bǔ)充抗氧化劑產(chǎn)生的良好效果的實(shí)驗(yàn),筆者認(rèn)為機(jī)體的運(yùn)動(dòng)訓(xùn)練可能處于ET階段,此時(shí)運(yùn)動(dòng)強(qiáng)度較高,會(huì)產(chǎn)生HOS 或LOS。在HOS時(shí),適當(dāng)補(bǔ)充外源性抗氧化劑可將OS水平降到LOS,既減少了氧化損傷,又能形成新的OAH。而在LOS時(shí),補(bǔ)充抗氧化劑可能將ROS水平降到oROZ,雖消除了氧化應(yīng)激,但只能維持現(xiàn)有OAH,無(wú)法建立更高品質(zhì)的OAH,因此無(wú)助于提高運(yùn)動(dòng)成績(jī)。

3.2抗氧化劑補(bǔ)充的害處

由于難以定量ROS的各水平狀態(tài),運(yùn)動(dòng)中抗氧化劑的實(shí)際補(bǔ)充就顯得較難操作(補(bǔ)什么、何時(shí)補(bǔ)、補(bǔ)多少?)。有不少的文獻(xiàn)報(bào)道了抗氧化劑補(bǔ)充的不良影響。早在1971年,Sharman等人[31]報(bào)道了補(bǔ)充VE(400 IU/d,持續(xù)6周)對(duì)耐力成績(jī)有不利影響。同樣Brady等人[32]研究表明補(bǔ)充硒和VE沒(méi)有提高大鼠的游泳成績(jī)。Malm等人[33-34]發(fā)現(xiàn)在大強(qiáng)度運(yùn)動(dòng)后補(bǔ)充泛醌-10對(duì)人體產(chǎn)生了有害影響。Childs等人[35]讓受試者在補(bǔ)充VC(12.5 mg/kg)混合N-乙酰-L-半胱氨酸(N-Acetyl-cysteine,NAC)(10 mg/kg)后立即進(jìn)行離心屈肘運(yùn)動(dòng),增加了氧化應(yīng)激。Coombes等人[36]觀察到補(bǔ)充VE降低了肌肉強(qiáng)直收縮的力量。對(duì)參與比賽的灰狗補(bǔ)充VC(1 g/d,為期4周)則顯著降低了它們的跑速[37]。Close等人[38]研究發(fā)現(xiàn),補(bǔ)充VC(1 g/d,持續(xù)14 d)沒(méi)有減弱運(yùn)動(dòng)后肌肉的疼痛,反而延遲了恢復(fù)的過(guò)程。Gomez等人[39-40]的兩篇論文報(bào)道了補(bǔ)充抗氧化劑阻止了運(yùn)動(dòng)引起抗氧化酶表達(dá)的增加。最近Mari等人[41]通過(guò)隨機(jī)雙盲試驗(yàn),對(duì)14名參與8周訓(xùn)練的運(yùn)動(dòng)員中的5人補(bǔ)充VC(1 g/d),同時(shí)又給24只運(yùn)動(dòng)的Wistar雄性大鼠補(bǔ)充VC(500 mg/kg),結(jié)果表明VC的補(bǔ)充阻止了抗氧化酶對(duì)運(yùn)動(dòng)訓(xùn)練的適應(yīng),降低了訓(xùn)練效果。

筆者分析了以上補(bǔ)充抗氧化劑不良影響的可能原因,認(rèn)為機(jī)體的運(yùn)動(dòng)訓(xùn)練可能已進(jìn)入OT階段,補(bǔ)充抗氧化劑有可能將ROS水平降得比minROZ還低,體內(nèi)抗氧化酶基因無(wú)法激活表達(dá),導(dǎo)致OAH退化,造成抗氧化劑的補(bǔ)充無(wú)益甚至有害的情況[42]。長(zhǎng)期的抗氧化劑補(bǔ)充或停訓(xùn)會(huì)使機(jī)體ROS水平經(jīng)常低于minROZ,降低了機(jī)體自身抗氧化酶的表達(dá),削弱了機(jī)體本身抗氧化酶的活性,從而降低OAH的品質(zhì)[43],不利于運(yùn)動(dòng)水平的提高。

4討論

minROZ與maxROZ之間的ROS水平可引起內(nèi)源性抗氧化酶的表達(dá),而sROS則能引起抗氧化酶表達(dá)的上調(diào)。體內(nèi)表達(dá)的各種抗氧化酶其抗氧化能力不盡相同,這是因?yàn)楦鞣N酶要發(fā)揮抗氧化效應(yīng)與其結(jié)構(gòu)特征、生物活性以及在體內(nèi)的濃度比例有關(guān)[2]。在抗氧化酶表達(dá)上調(diào)問(wèn)題上,Pérez等人[44]最新研究讓我們對(duì)上調(diào)量需引起注意,因?yàn)榭寡趸高^(guò)多的表達(dá)可能對(duì)機(jī)體無(wú)意義。

我們應(yīng)辯證地看待ROS在調(diào)節(jié)細(xì)胞氧化還原信號(hào)轉(zhuǎn)導(dǎo)方面的生物學(xué)意義。否則一味的利用抗氧化劑來(lái)清除它,可能會(huì)造成機(jī)體整個(gè)OAH的退化。Ji[17]最近研究表明,減少ROS的生成(直接通過(guò)化學(xué)抑制劑或補(bǔ)充大量的抗氧化劑)會(huì)阻止細(xì)胞對(duì)OAH的建立。

某些情況下,外源性抗氧化劑的補(bǔ)充可能暫時(shí)起到一定的抗氧化預(yù)防作用,但合成的抗氧化劑也許會(huì)有副作用[42]。運(yùn)動(dòng)員的抗氧化能力必須依靠運(yùn)動(dòng)訓(xùn)練本身來(lái)解決[45]。適量運(yùn)動(dòng)可以說(shuō)是預(yù)防和治療的最佳“抗氧化劑”,它可導(dǎo)致細(xì)胞抗氧化系統(tǒng)結(jié)構(gòu)維持與重塑的革新[17]。無(wú)論是ET還是OT,其具體形式仍表現(xiàn)為耐力運(yùn)動(dòng)或抗阻運(yùn)動(dòng),它們都可調(diào)節(jié)體內(nèi)的OAH[2,45-46]。運(yùn)動(dòng)訓(xùn)練的目標(biāo)就是要打破品質(zhì)低的OAH,使體內(nèi)抗氧化系統(tǒng)的活性逐步上調(diào),建立品質(zhì)高的OAH[47]。我們找到“運(yùn)動(dòng)”這種天然的抗氧化手段,可以說(shuō)是最經(jīng)濟(jì)實(shí)惠了。運(yùn)動(dòng)的其抗氧化的能力受運(yùn)動(dòng)量、運(yùn)動(dòng)時(shí)間、運(yùn)動(dòng)認(rèn)知等諸多因素的綜合影響。我們能否通過(guò)定量分析,建立出運(yùn)動(dòng)與發(fā)揮最佳功能所需ROS水平之間的數(shù)學(xué)模型并將其應(yīng)用于臨床就需要我們各學(xué)科的科研人員共同努力,對(duì)這一最適手段作出更深的探究。

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[編輯:鄭植友]