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   大连医科大学学报  2021, Vol. 43 Issue (2): 165-170      DOI: 10.11724/jdmu.2021.02.13
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谷氨酸钠的安全性研究进展
赵翠霞, 杨鸿武, 范文今, 牛璐, 马景红, 谢韬    
辽宁省疾病预防控制中心, 辽宁 沈阳 110015
摘要:谷氨酸钠是一种氨基酸的钠盐,大量摄入时,会导致血液谷氨酸浓度显著上升,可引起一系列有害影响。谷氨酸钠高暴露可干扰下丘脑的信号传导和瘦素功能,引起机体出现代谢综合征症状,母体高暴露可致新生儿出现代谢紊乱,新生儿期高暴露可致成年代谢综合征。谷氨酸钠还可诱导神经兴奋毒性,引起化学性脑损伤;以剂量依赖的方式损害男性生殖系统,通过损伤卵巢和子宫的功能来抑制雌性生殖功能;通过改变肾脏抗氧化系统损伤肾细胞和肾功能。本文对谷氨酸钠的安全性研究进展进行综述。
关键词谷氨酸钠    代谢综合征    神经系统    生殖系统    肾损伤    
Research progress on the safety of sodium glutamate
ZHAO Cuixia, YANG Hongwu, FAN Wenjin, NIU Lu, MA Jinghong, XIE Tao    
Liaoning Provincial Center for Disease Control and Prevention, Shenyang 110015, China
Abstract: Sodium glutamate is an amino acid sodium salt. When a large amountof glutamic acid enters the body, its concentration in the blood rises, which can cause a series of adverse reactions.Sodium glutamate interferes with hypothalamic signaling and leptin function and can cause metabolic syndromes in human bodies such as obesity, hyperinsulinemia, hyperglycemia, and hyperleptinemia.Neonates may develop metabolic disorders due to maternal exposure to high Sodium glutamate, and high-exposure in childhood can result inadult metabolic syndromes.Sodium glutamate can induceneuroexcitatory toxicity, causing neuronal damage or necrosis, leading to brain cell damage, retinal degeneration and neuroendocrine disorders, inhibiting learning and memory, and adversely affecting growth and development.Sodium glutamate can also damage the male reproductive system in a dose-dependent manner and inhibit female reproductive function by impairing the function of the ovary and uterus. Sodium glutamate may impair renal cell and kidney function by altering the antioxidant system. This paper reviews the research progress on the safety of sodium glutamate.
Keywords: sodium glutamate    metabolic syndrome    nervous system    reproductive system    kidney damage    

谷氨酸钠(monosodium glutamate,MSG)化学名a-氨基戊二酸一钠,商品名称为味精,进入机体后可分解为谷氨酸和钠离子。MSG是一种增强食物鲜味的食品添加剂,可以增加蔬菜等的味道,增进食欲,世界各国尤其亚洲国家使用十分广泛。

美国食品药品管理局(FDA)、世界卫生组织(WHO)、联合国粮农组织(FAO)等就MSG安全性,进行了很多实验研究,并曾于1973年发布MSG的日允许摄入量(ADI)为153 mg/kg。1987年,FAO和WHO宣布取消对MSG的食用限量,MSG作为一种增加食品风味的调味料,不再需要评价其ADI。据统计分析显示,通过正常饮食,人类游离谷氨酸的日平均摄入量>1 g,总谷氨酸的日平均摄入量为10 g。目前专家认为:1岁以下的婴幼儿不宜食用MSG,儿童不宜进食大量的MSG,如需母乳喂养时,母体也不宜进食MSG。2007年我国居民膳食指南建议,婴幼儿辅食中不加入MSG调味剂。长期摄入外源性MSG,会引起人体内谷氨酸浓度增高,进而出现一系列异常反应,即使每日摄入量低至0.3~1.0 g,连续摄入5年后,人体异常反应风险亦增加[1]。1969年Olney首次报道,给新生小鼠皮下注射2 mg/g的MSG可引起急性神经损害,并在小鼠成年后发生肥胖、高瘦素血症等。从此,MSG的食品安全问题一直是一个争论不休的话题。本文就谷氨酸钠的安全性研究进展进行综述。

1 MSG对代谢功能的影响

代谢综合征(metabolic syndrome, MET-S)是指机体的蛋白质、脂肪、碳水化合物等物质发生代谢紊乱,出现一系列临床综合征,被认为是目前全球心血管疾病最突出的危险因素[2]。研究数据表明,发达国家20%~30%的成年人患有代谢综合征。除了卡路里摄入增加外,还与一些特定的饮食因素有关。

MSG是一种常见的增味剂和天然氨基酸,被越来越多地使用在食品工业中。对人类和动物模型研究的数据表明,MSG可增加适口性、干扰下丘脑的信号传导和瘦素功能,与超重/肥胖之间存在联系,增加了人们对MSG作为肥胖危险因素的担忧[3]。对中国健康受试者进行的横断面和纵向研究表明,无论摄入的卡路里总量和运动量如何,MSG的摄入都会增加超重的风险[4]。Insawang等[5]研究了泰国农村人口中MSG摄入量与代谢综合征的关系后推测,MSG日摄入量每增加1 g,MET-S风险增加1.14倍,超重风险增加1.16倍。多项动物实验研究报道了食用或注射MSG可致鼠、猪等动物肥胖,新生大鼠连续5天皮下注射3 mg/g的MSG可导致大鼠肥胖[6-7]

动物模型证实,母体摄入大剂量MSG与新生儿代谢综合征之间有因果关系,可能与新生儿食物摄入和能量消耗的调节机制尚不成熟有关。妊娠期经口摄入MSG,胎儿大脑中出现谷氨酸蓄积。有研究者用猫作为内分泌疾病模型进行了实验,即F0代在交配前3周内、妊娠期和断奶期持续摄入添加1.125%MSG的饮食,F1代在整个研究期间摄入该特殊饮食,9月龄时仔猫肝脏脂肪变性增多,血清TAG、T-CHOL、LDL-C和HDL-C浓度及肝中甘油三酯含量以及总体脂显著升高,空腹胰岛素和胰岛素抵抗指数(HOMA-IR)至少比正常饮食仔猫高2.4倍,提示添加谷氨酸钠的饮食后诱导仔猫胰岛素抵抗,仔猫体内柠檬酸盐转化为棕榈酰辅酶A的途径受到抑制;仔猫细胞因子信号转导抑制因子2(SOCS2)的表达增加1倍,胰岛素样生长因子1(IGF-1)的表达减少一半,仔猫的生长激素轴受损[8]。啮齿动物孕期大剂量MSG的暴露可导致雄性子代肥胖,表现为高胰岛素血症、高血糖症、高瘦素血症、血脂异常和瘦素信号受损,提示中枢瘦素抵抗、葡萄糖不耐受、肾上腺素能抑制胰岛素分泌[9]

非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)是代谢综合征的肝表型。给Swiss小鼠新生期皮下注射MSG[4 g/(kg·d)],观察60、120或180天,小鼠在3个年龄段均表现出高甘油三酯血症和中心性肥胖,且肝脏总脂肪和甘油三酯含量均较高,120天和180天龄小鼠表现出外周胰岛素抵抗。肝组织病理学分析显示,60天龄的小鼠有微泡脂肪变性,自120天龄演变为NASH[10]。将MSG皮下注射到新生雄性小鼠体内,下丘脑弓状核到室旁核的通路破坏,血清胰岛素和胆固醇水平显著升高,肝脏可见微泡脂肪变性和炎性细胞浸润,附睾脂肪中观察到肥大的脂肪细胞和树冠样结构。流式细胞术分析显示,小鼠肝脏和附睾脂肪组织中出现单核细胞和M1巨噬细胞的频率均增加;MSG小鼠表现出NASH的特征性肝组织病理学和代谢综合征样特征[11]

2 MSG对神经系统的影响

谷氨酸是人和哺乳动物脑内含量最高的兴奋性氨基酸,参与中枢神经系统的信息传递。谷氨酸受体如N-甲基-D-天冬氨酸(NMDA)受体广泛分布于包括杏仁核、海马和下丘脑在内的中枢神经系统中,参与调节能量代谢和自主功能。当血液中存在微量的谷氨酸时,对身体不会有影响。但当我们通过饮食摄入过多的MSG时,谷氨酸会大量地进入大脑,浓度大幅度上升,可产生神经兴奋毒性,造成神经元损伤或死亡,机体会出现一些症状和体征,如头昏眼花、眼球突出、上肢麻木、下颌发抖、心慌气喘、晕眩无力等。

最近有证据表明,饮食中MSG摄入量的增加与收缩压的增加有关,且收缩压增加在女性中比男性更为明显[12]。MSG诱导的血压升高,可解释观察研究人群中头痛发生率增加的原因。约70%的颞下颌关节紊乱(temporomandibular disorders, TMD)患者会出现咀嚼肌疼痛,并被描述为伴有肌筋膜疼痛的TMD患者,MSG的摄入被认为会加速或加重其慢性颅面疼痛的症状。单次摄入150 mg/kg MSG的健康年轻男性,其头痛和颅面部肌肉敏感性显著增加,收缩压升高。而且,在肌筋膜疼痛的TMD患者咀嚼肌疼痛区域,伴随谷氨酸浓度升高[13]。这表明MSG进入机体后除可引起头痛外,还可引发颅面部疼痛。分别向健康志愿者皮下、肌肉内注射MSG后,发现皮下注射引起的咬肌区疼痛比肌肉注射更痛苦,不愉快感更强[14]。谷氨酸在体内被骨骼肌(包括咀嚼肌)吸收,间质谷氨酸浓度的升高使肌肉痛觉感受器对机械刺激敏感, 这一效应可能是健康年轻人服用MSG后颅面部肌肉疼痛敏感的基础。在一项研究中,14名健康受试者连续5天摄入MSG(150 mg/kg)/安慰剂(24 mg/kg Nacl)(随机、双盲),MSG诱导了咬肌的机械致敏和头痛、短时间的血压升高等不良反应,且连续5天的MSG摄入没有产生耐受性[15]。TMD患者对摄入MSG的影响特别敏感,MSG摄入引起的咬肌间质谷氨酸浓度升高明显高于健康人。在TMD患者中,咬肌间质谷氨酸浓度的升高显著增加了自发性疼痛的强度[16]

MSG可引起化学性脑损伤,认知功能下降、神经变性和精神症状(抑郁、焦虑、睡眠障碍和易怒)增多,且与典型创伤性脑损伤的病理生理学非常相似,可导致脑细胞损伤、视网膜变性、内分泌紊乱和一些病理状况,如中风、癫痫、脑外伤、神经性疼痛、精神分裂症、焦虑、抑郁、帕金森氏病、阿尔茨海默病、亨廷顿氏病和肌萎缩侧索硬化综合征[17]。1954年,Hayashi等对狗、猴子和人的实验中,证实谷氨酸在中枢神经系统作为神经递质的作用,向大脑皮层灰质注射MSG可产生阵挛性抽搐。20世纪50年代,Lucas等首次报道MSG可引起视网膜内层神经元不可逆性坏死。1969年,Oleny证实MSG对视网膜及下丘脑内侧基底部均具有毒性作用。

多项研究表明,MSG暴露可导致动物模型的认知功能障碍[18-20]。新生儿摄入大剂量MSG,会导致成年时学习能力严重不足,并改变海马和脑前皮层的θ节律[21]。SD大鼠出生后第1、3、5、7、9天皮下注射4 mg/g的MSG,3个月龄时出现高血糖、阿尔茨海默样学习和记忆障碍,树突脊柱密度和海马突触相关蛋白表达降低,磷酸化tau蛋白水平增加[22]。5周龄雄性Wistar大鼠连续口服2 g/kg的MSG,会导致长期记忆障碍,海马和皮质的Na+-K+-ATP酶受到抑制[23]。大鼠连续60天口服100 mg/(kg·d)的MSG,大脑组织中谷胱甘肽(GSH)水平、超氧化物歧化酶(SOD)和过氧化氢酶(CAT)活性显著下降,丙二醛(MDA)、一氧化氮(NO)水平明显升高,β淀粉样肽水平升高,脑细胞内Na+和Ca2+和K+浓度增高。组织病理学检查显示,大鼠出现严重的神经元变性,血管周围水肿、充血和核浓缩[24]

多项研究表明,由于新生动物血脑屏障发育尚未成熟,口服或皮下注射MSG可引起中枢神经系统的一些区域出现神经元细胞坏死[25-27]。0岁到3~4岁的儿童,大脑处于发育最快时期,若每天食用含有MSG的食物,或饮用含有MSG的饮料,因MSG的反复刺激,婴幼儿可出现脑部损伤,内分泌紊乱,给生长和发育带来不良影响。给予成年小鼠和大鼠皮下注射MSG,引起最后区(AP)神经元的快速变性。对妊娠大鼠皮下给予MSG,母鼠和仔鼠都可观察到最后区乙酰胆碱酯酶阳性神经元的急性坏死,且胎儿的神经元对MSG更敏感[28]

3 MSG对生殖系统的影响 3.1 MSG对雄性生殖系统的影响

谷氨酸是一种兴奋性神经递质,可引起神经元细胞内钙大量流入而导致神经元死亡。谷氨酸可破坏下丘脑-垂体轴途径(HPA),HPA的破坏可降低性激素的水平,包括睾丸激素,促卵泡激素和促黄体激素,最终导致精子异常[29]。动物实验发现,MSG可影响大脑中生殖系统的支配部位即丘脑下部, 进而会引起生殖系统的变化。MSG已被公认,对男性生殖系统有毒性作用。由于在生殖器官和精子中有大量的谷氨酸受体,生殖系统很容易成为谷氨酸诱导损伤的靶点,这使它们容易受到体内过量谷氨酸引起的兴奋性损伤。MSG以剂量依赖的方式引起雄性Wistar大鼠的精子活力显著低下,异常形态的精子增多,对睾丸也有毒性作用。MSG通过引起睾丸出血、变性及精子形态的改变而与男性不育有关[30]

睾丸、附睾、精子和精液中含有高活性的抗氧化酶,SOD催化超氧化物自由基转化为过氧化氢,CAT则将过氧化氢转化为水,SOD与CAT联合提供了第一防御氧化应激的系统,这些酶共同作用,消除活性氧类物质。大剂量的MSG摄入可导致啮齿动物SOD、CAT和谷胱甘肽过氧化物酶(GPX)活性显著降低,同时引起一些组织病理学变化,生精停滞、水肿和精子活力低下症,这些改变可能与MSG对睾丸细胞膜和睾丸组织的氧化作用有关[31]

3.2 MSG雌性生殖系统的影响

近年来MSG对女性生殖器官生理功能的毒性作用为研究学者所关注。MSG以两种方式即通过兴奋性毒性和产生氧化应激影响着女性生殖系统。MSG可引起下丘脑弓状病变,导致儿茶酚胺释放减少,儿茶酚胺参与促黄体生成素释放激素(LHRH)的释放,故MSG通过扰乱下丘脑-垂体-卵巢(HPO)轴的功能引起激素失衡[32]

Jyoti Rani等[33]研究发现,Wistar大鼠连续14天经口摄入MSG,Graafian卵泡平均数减少,这表明MSG对滤泡有毒性作用;闭锁卵泡数水平增加,提示MSG可阻止排卵;卵泡膜轻度肥大,初级卵泡数量显著减少;MSG对卵泡有毒性作用,MSG通过产生氧化应激和不可逆地破坏血清促卵泡激素(FSH)受体来破坏卵泡,抑制卵泡发育为成熟的卵泡,导致原始卵泡发生凋亡,次级、三级卵泡数量明显减少;黄体数量显著减少,大鼠卵巢切片显示有大量卵泡退化、中度空泡形成和血管充血。

新生雌性大鼠每2天皮下注射1次4 g/kg的MSG,直至出生后第10天(PND10)。PND60时大鼠体重增加,腹膜后和内脏脂肪垫积聚,内脏脂肪细胞肥大。卵巢形态分析显示,卵母细胞计数减少一半,卵巢滤泡囊肿增加6倍,原始和闭锁滤泡数量增多。此外,大鼠窦滤泡的抗穆氏管荷尔蒙免疫组化染色增加4倍[34]。Mondal M等[35]研究发现,连续30~40天对未交配雌性Charles Foster大鼠灌胃方式给予MSG后,大鼠动情前期、动情期和动情后期的持续时间显著减少,间情期持续时间增加,FSH、黄体生成素(LH)、雌二醇水平显著升高,原始卵泡体积显著增大,Graafian卵泡体积增大,黄体的体积减小,SOD、CAT、谷胱甘肽硫转移酶(GST)、谷胱甘肽还原酶(GR)和GPX活性异常,推测MSG可能通过增加LH、FSH和雌二醇的释放、抑制卵泡成熟和影响抗氧化的生化机制来损害卵巢的功能;大鼠动情期、动情后期和间情期子宫收缩力显著增强,提示MSG可通过刺激雌二醇对催产素的敏感性而增强子宫收缩;该研究表明,MSG可通过损害卵巢和子宫的功能来抑制大鼠的雌性生殖功能。

4 MSG对肾脏的影响

肾脏对缺血、毒性损伤和其他化学物质高度敏感。直接或间接干扰肾细胞能量代谢的过程将导致肾细胞损伤和急性肾功能不全。有文献报道,MSG可引起肾细胞结构的改变,肾小球的细胞数增加,肾皮质炎症细胞浸润,肾小管细胞水肿,最终导致肾小管变性[36-37]。大剂量口服MSG,会导致大鼠尿碱化和磷酸钙结晶尿,进而导致肾结石形成,随后出现肾积水和间质纤维化[38]。5周龄雄性Wistar大鼠自由摄取含MSG的饲料[3 g/(kg·d)]和饮水(1%MSG),每周5天,持续16周。随着钠重吸收绝对值的增加,肾小球滤过率和肾皮质血浆流量均升高。免疫染色显示,大鼠N-甲基-D-天冬氨酸(NMDA)受体上调[39]。肾脏中活性氧形成被认为是MSG肾毒性作用的主要原因,因为活性氧可导致肾细胞和肾功能损伤。通过注射或口服实验证明,MSG可以改变肾抗氧化系统和肾功能。研究发现,摄入MSG后肾脏中超氧化物歧化酶、过氧化氢酶、谷胱甘肽-S-转移酶和谷胱甘肽(GSH)活性降低,脂质过氧化的标记物MDA和共轭二烯增加。MSG可能导致自由基的过度产生、内源性抗氧化剂不足进而造成肾损伤[40]。饮水摄入MSG[2 mg/(g·d)]9个月的Wistar大鼠,氧化应激指示物热休克蛋白同源物Hsc70的表达上调和肾脏中谷胱甘肽-S-转移酶的表达下调[41]。此外,维生素D和槲皮素等一些抗氧化剂,可减轻MSG诱导的肾损伤[42-43]

综上所述,虽然MSG作为食品添加剂对食品工业有巨大的价值,但一些研究也提示过量摄取MSG可能具有毒性作用。这些毒性效应包括肥胖、高胰岛素血症、中枢神经系统和生殖系统异常及肾损伤等。当今社会人们长期摄入大剂量的MSG,却未意识到这种食品添加剂的过量使用会对人类健康产生有害影响。因此,加强对控制MSG摄入量的宣传教育和引导是十分必要的,应引起高度重视。

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文章信息

赵翠霞, 杨鸿武, 范文今, 牛璐, 马景红, 谢韬
ZHAO Cuixia, YANG Hongwu, FAN Wenjin, NIU Lu, MA Jinghong, XIE Tao
谷氨酸钠的安全性研究进展
Research progress on the safety of sodium glutamate
大连医科大学学报, 2021, 43(2): 165-170.
Journal of Dalian Medical University, 2021, 43(2): 165-170.
通信作者
谢韬, 主任技师。E-mail: 1071842987@qq.com.
基金项目
辽宁省重点研发计划指导项目(2018205003)

工作空间