1999 - Mechanisms of Fluoride Effects on Thyroid

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30. 刘国艳,柴春彦,康世良.氟损伤甲状腺机理的研究进展[J].中国地方病学杂志,1999,18(5):388-389

　［文章编号］ 1000-4955(1999)05-0388-02氟

　　关键词：甲状腺

　　氟在自然界中广泛存在，是人和动物机体维持正常的生理活动所必需的一种微量元素。但摄入过量的氟化物又可对机体造成损害，而且氟的毒性作用是广泛性的，几乎对机体所有的组织器官均产生损害作用［1］。研究最多、最深入的是氟对骨骼、牙齿的影响。近年来，氟对软组织的损伤作用引起人们的广泛关注。甲状腺是动物机体重要的内分泌器官，具有较强的摄氟能力。有资料报道［2］：氟化物可明显地影响甲状腺的形态结构，导致甲状腺肿大。也有研究表明，氟化物能破坏甲状腺的机能，严重地干扰甲状腺正常功能的发挥［3］。氟对甲状腺产生毒性作用的机理目前还不十分清楚，仍处于推理、假设阶段。为便于了解和掌握氟损伤甲状腺的毒理学方面的研究进展情况，综合近几十年来国内外研究的有关资料，现将有关此方面的理论和观点归纳为以下几点：

　　1　氟与酪氨酸酚羟基成氢键理论

　　元素氟是强氧化剂，具有高度的破坏性［4］。氟离子（F）呈强电负性 ，生物学特性非常活泼，对动物机体可产生多种作用。酪氨酸分子带有酚羟基，参与构成多种重要的蛋白质，也是甲状腺激素（T4）、三碘甲腺原氨酸（CT3）的基本组成单位。酪氨酸在机体内充足与否以及是否发挥正常的生理功能，直接影响着甲状腺激素的合成与分泌，进而影响甲状腺的结构和功能。

　　大量的实验和理论数据均证实了氟与氨基化合物之间能形成异常强的氢键，这是氟化物干扰动物机体正常生理功能的一种机制［5］。现已证明，氟易与酪氨酸酚羟基以氢键的形式发生专一性的结合，从而改变了相应蛋白质的分子构像，同时也影响了酪氨酸分子的某些生物学特性［6］。酪氨酸是甲状腺激素生物合成的主要原料，其酚羟基中的氧原子是以SP2杂化轨道参与成键的，该氧原子有一对未共享的电子在P轨道方向与苯环上的π轨道平行，形成P-π共轭。因此，氧原子上的部分电荷分散到整个共轭体系中，使苯环上富电子［7］。氟与酪氨酸酚羟基形成氢键后，由于氟的电负性大，吸电子能力强，其产生的效应使酪氨酸分子中的酚羟基氧和苯环上与酚羟基相邻的两个碳原子及与酚羟基相连的碳原子上的净电荷减少，导致碘分子（I2）在与酚羟基相邻的两个碳原子上的亲电取代反应减弱，抑制了甲状腺摄取和利用碘，并增加了机体对酪氨酸的清除，以至于干扰了T3、T4的合成。氟造成了甲状腺激素合成障碍，从而引起甲状腺的形态结构和机能的异常改变。

　　2　氟致抗氧化体系及自由基代谢紊乱理论

　　有资料报道［8］：氟能引起动物机体抗氧化功能降低，使机体谷胱甘肽过氧化物酶、超氧化物歧化酶等抗氧化酶类活性降低，而脂质过氧化产物显著增加。氟还能导致机体产生过量的自由基，对组织器官的膜结构造成损伤；还原型谷胱甘肽（GSH）是存在动物细胞内最重要的非蛋白巯基化合物，参与维持细胞的正常完整骨架，也可对细胞内自发或酶促反应所生成的活性中间产物进行解毒，清除过量的自由基，在抗脂质过氧化过程中发挥着重要的作用。Jeji等（1985）［9］通过测定氟病患者与非氟病患者血中GSH水平，探讨了氟所致细胞结构的变化。细胞内的GSH作为一种氧化还原保护剂使细胞的膜结构维持正常状态。氟进入细胞，可被GSH有效结合而清除，从而维持了脂膜的完整和正常功能。如果氟过多，刺激细胞内GSH达到临界水平，则引起细胞的膜结构破坏和功能紊乱。因为酪氨酸的碘化及耦联都是需要甲状腺过氧化物酶以过氧化氢为底物催化完成的，所以甲状腺是一个经常暴露于自由基损伤下的腺体。氟过量，机体抗氧化能力降低，自由基过量生成，细胞内GSH代偿性清除氟的能力下降，必然对甲状腺的质膜（细胞膜、细胞器膜）结构造成损伤。甲状腺滤泡上皮具有很强的聚碘能力，但甲状腺聚碘的基础是滤泡的膜结构必须保持完整，而过量的氟破坏了滤泡的完整结构，导致甲状腺摄碘功能障碍以及甲状腺激素合成不足。

　　3　氟影响甲状腺功能酶系统的生物学活性理论

　　3.1　氟对腺苷酸环化酶的影响　Fassina等（1972）［10］研究报道，氟进入机体后，可增加或抑制细胞膜上的腺苷酸环化酶（AC）的活性，使细胞内环腺苷酸（cAMP）水平增高或降低，从而影响ATP的形成。cAMP作为甲状腺激素的第二信使，对甲状腺激素发挥正常功能起着重要的调节作用。cAMP升高或降低，直接地影响着甲状腺的功能。

　　3.2　氟对Na＋,K＋-ATP的影响　Ballantyne等(1981)［11］报道，氟能抑制细胞膜上Na＋，K＋-ATP酶的活性。碘从血液中转运到甲状腺上皮基膜，是一个主动转运过程，需消耗大量的能量。在甲状腺滤泡细胞底部的细胞膜上有依赖于Na＋,K＋-ATP酶的碘泵，在碘的转运过程中起着关键性作用：其促进碘进入甲状腺上皮滤泡内，并阻止滤泡内碘的流出，增强聚碘作用。氟过量，Na＋,K＋-ATP酶受抑制,阻碍了碘的正常转运，从而影响了甲状腺激素的合成和分泌。另外，甲状腺激素是通过直接刺激组织细胞膜的钠泵来完成产热作用的，此作用的正常发挥也与Na＋,K＋-ATP酶关系密切。氟抑制了Na＋，K＋-ATP酶的活性，导致甲状腺激素的产热作用受抑制。

　　3.3　氟对甲状腺蛋白水解酶的影响　甲状腺球蛋白（TG）是一种巨大球状的糖蛋白分子，肩负着双重作用：一是作为碘化酪氨酸和甲状腺激素合成的载体；二是贮存碘和合成的甲状腺激素。合成的TG贮存在滤泡腔内，利用时，TG则被重吸收进入滤泡上皮细胞，形成胶质小滴，胶质此时被蛋白酶消化分解，释放出T4、T3及二碘酪氨酸（DIT）和一碘酪氨酸（MIT）。Willems(1972)的研究表明，氟可抑制促进TG分解为T3、T4的蛋白酶活性［12，13］。氟抑制水解TG的蛋白酶活性，致使TG分解减少，结合在TG上的T3、T4、DIT、MIT不能游离出来，从而影响了甲状腺激素的释放以及碘的再利用。

　　3.4　氟对甲状腺过氧化酶的影响　有资料报道，过量的氟能抑制甲状腺过氧化物酶（TPO）的活性［14］。TPO是一种含铁卟啉的血红蛋白类物质，其主要的生物学作用是使碘活化，酪氨酸碘化和促进碘化酪氨酸的耦联，在甲状腺激素合成过程中起着关键的作用。氟抑制TPO的活性，则甲状腺激素合成的多个环节受抑制,从而引起甲状腺激素合成障碍。

　　4　氟干扰甲状腺细胞糖类和脂类代谢理论

　　Shashi等（1988）用兔的实验研究表明［15］，实验性兔氟中毒时，兔甲状腺中有大量脂肪蓄积，出现高脂血症，甲状腺中脂类，总脂及甘油三酯含量异常增加，而游离脂肪酸含量则显著降低。氟也是无氧酵解的潜在的抑制剂。氧化物还干扰葡萄糖分解体系，导致磷酸甘油酸蓄积和ATP合成减少［16］。由于甲状腺细胞内糖类，脂类代谢障碍，必然影响甲状腺激素的合成，分泌，影响甲状腺的功能。

　　总之，上述推理及假设是否正确，还需进一步证明。揭示氟损伤甲状腺的毒理机制是今后的艰巨任务。

　　作者简介：柴春彦　综述

　　康世良　审校

　　作者单位：东北农业大学 动物医学院，黑龙江 哈尔滨 150030

　　参考文献

　　［1］　IRPTC.Scientific reviews of soviet literature on toxicity and hazards of chemicals,sodium fluoride［M］.United Nations environment programme,38.Moscow:Centre of international projects GKNT,1983:5-35.

　　［2］　Hillman D.Hypothyroidism and anemia related to fluoride in dairy cattle［J］.Dairy Science,1979,62:416-423.

　　［3］　Juvenal GJ.Role of neurotransmitters,prostoglandins and glcose on precursor incorporation into the RNA of thyroid slices［J］.Acta Endocrinologica,1978;87:776-785.

　　［4］　Largent EJ.Fluorine and compounds luigi parmeggiani.Encyclopaedia of occupational health and safety［M］.Third (Revised) Edition.Switzland:ILO Geneva,1983:891-894.

　　［5］　Editorial.Hydrogen bonding by fluoride ion:Mechannism of toxicity［J］.Fluoride,1982,15(2):98.

　　［6］　李健学，张艳明，张国高.氟与酪氨酸酚羟基成氢键作用的量子力学计算［J］.地方病通报.1991，6（1）:11-14.

　　［7］　王惠忠.有机化学与试剂［M］.北京：中国建筑工人出版社.1987,168.

　　［8］　吴南屏，赵忠良，高文华.氟对发育中大鼠脂质过氧化作用的影响［J］.氟研究通讯，1993,8(1,2):27.

　　［9］　Jeji.Implication of glutathione inendemic fluorosis［J］.Fluoride,1985,18(2):117.

　　［10］　Fassina G.Effects of glycolysis inhibitors on cyclic AMP synthesis in rat adipose tissue［J］.Biochem.Pharmacol,1972,21:2295-2301.

　　［11］　Ballantyne DJ.Chloroplast electron transport protein and RNA in fluoride treated shoots［J］.Environ Expere Botany,1981,21:83-88.

　　［12］　Willems C.Inhibition of thyroid secretion by sodium fluoride in vitro［J］.Biochem Biophys Acta,1972,264:197-204.

　　［13］　Bobek S.Effect of long term fluoride administration on thyroid Hormones level in blood in rats［J］.Endocrinol Exp,1976,10:289-295.

　　［14］　许德顺，许广涛.氟对甲状腺的影响［J］.国外医学医学地理分册，1984,5(1):1-5.

　　［15］　ShaShi.Biochemical effects of fluoride on thyroid gland during experimental fluorosis［J］.Fluoride,1988,21(3):127-130.

　　［16］　Dirksen TR.In vitro effects of fluoride on lipid synthesis by rat calvaria［J］.Arch Oral Biol,1972,17:55-59.

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Mechanism of fluoride thyroid damage Progress

　　Chinese Journal of Medicine

　　1999 Vol 18 No. 5 vol.18No.51999

Liuguo Yan Chai Chunyan Summary Kang Shiliang revisers

　　[CLC]　O613.41

　　[Document code] A

　　[Article ID] 1000-4955 (1999) 05-0388-02 fluorine

　　Keywords: Thyroid

　　Fluoride is widespread in nature, is human and animal body maintain normal physiological activities of a trace element necessary. However, excessive intake of fluoride can be damaging to the body, and the toxic effects of fluoride is extensive, almost all of the tissues and organs of the body are produced damaging effects [1] . Most studied, the most in-depth is fluoride on bones, teeth affected. In recent years, fluoride on soft tissue injury caused widespread concern. The thyroid gland is an important endocrine organ animal body, with a strong ability of fluoride intake. Data reported [2] : Fluoride can significantly affect the morphology of the thyroid, causing goiter. There are also studies that fluoride can damage the thyroid function, seriously interfere with the normal function of the thyroid play [3] . Toxic effects of fluoride on the thyroid gland produces the mechanism is not yet very clear, still in the reasoning, assuming that phase. For ease of understanding and knowledge of the toxicology of fluoride injury thyroid research progress at home and abroad in recent decades, the study integrated information, the relevant theories and views in this regard are summarized in the following points:

　　A phenolic hydroxyl group of tyrosine into fluorine and hydrogen bonding theory

　　Elemental fluorine is a strong oxidant, a highly destructive [4] . Fluoride ion (F  ) was strongly electronegative, biological characteristics very lively, the animal organism can produce a variety of roles. With a phenolic hydroxyl group of tyrosine molecule, a protein involved in a variety of important constitutes also thyroid hormone (T 4 ), three iodine THYRONINE (CT 3 ) of the basic unit. Adequacy of tyrosine in the body and whether to play a normal physiological function, directly affect thyroid hormone synthesis and secretion, thereby affecting the structure and function of the thyroid gland.

　　Large number of experimental and theoretical data were confirmed by fluorine and amino compounds can be formed between the abnormally strong hydrogen bonds, which is the interference of fluoride normal physiological function of the animal's body as a mechanism [5] . It has been shown, fluorine easy and tyrosine phenolic hydroxyl to form hydrogen bonds occurring specific binding, thus changing the molecular conformation corresponding protein, but also affected the tyrosine molecule certain biological characteristics [6 ] . Tyrosine is a thyroid hormone biosynthesis main raw material, in which an oxygen atom of a phenolic hydroxyl group is a SP 2 hybrid orbital in a bond, an oxygen atom which has a pair of unshared electrons in the track direction P π on the benzene ring parallel to the rail, to form P-π conjugation. Therefore, the partial charge on the oxygen atoms dispersed throughout the conjugated system in the benzene ring electron-rich [7] . Fluorine and a phenolic hydroxyl group of tyrosine to form hydrogen bonds, due to the large electronegativity of fluorine, electron-withdrawing ability, which produces the effect of the phenolic hydroxyl group of tyrosine oxygen molecule and a phenolic hydroxyl group on the benzene ring with two adjacent carbon atoms, and with a phenolic hydroxyl group on the carbon atom attached to the net charge reduced, resulting in molecular iodine (I 2 ) with the phenolic hydroxyl groups on two adjacent carbon atoms of the electrophilic substitution reaction decreased, inhibit thyroid iodine uptake and utilization and increases the removal of the body of tyrosinase, that interferes with T 3 , T 4 synthesis. Fluorine caused thyroid hormone synthesis disorders, causing thyroid morphology and function abnormalities.

　　Two fluorine radicals of oxidative metabolism system and theory

　　Data reported [8] : fluoride can cause animals antioxidant function is reduced, so that the body of glutathione peroxidase, superoxide dismutase activity of antioxidant enzymes decreased, while lipid peroxidation products increased significantly. Fluoride also causes the body to produce an excess of free radicals, membrane structure for tissue and organ damage; reduced glutathione (GSH) is present in animal cells most important non-protein thiol compounds involved in maintaining normal cell intact skeleton, but also on the intracellular spontaneous or enzymatic activity generated by the reaction intermediates for detoxification, clearing excessive free radicals in lipid peroxidation process plays an important role. Jeji etc. (1985) [9] by measuring fluorine ill patients with non-fluorine plasma GSH levels, discusses changes in cell structure caused by fluoride. Intracellular GSH as a redox cell membrane protective agent to maintain normal structure. Fluorine into the cells, which can be effectively combined with GSH and clear, so as to maintain the integrity of the lipid membrane and normal function. If too much fluoride, stimulating intracellular GSH reaches a critical level, causing cell membrane damage and dysfunction. Because tyrosine iodination and coupling are required to thyroid peroxidase substrate hydrogen peroxide catalyzed, so thyroid is a constantly exposed to free radical damage the glands. Fluoride overdose, reduced antioxidant capacity, excessive production of free radicals, intracellular GSH compensatory fluoride removal capacity decreased, bound to the plasma membrane of the thyroid (membranes, organelles, membrane) structural damage. Thyroid follicular epithelium polyiodides has a strong ability, but is based on polyiodides thyroid follicular membrane structure must remain intact, while the excess fluoride destroys the complete structure of follicles, leading to dysfunction of the thyroid iodine uptake and thyroid hormone synthesis inadequate.

　　3 fluorine affect thyroid function theory of the biological activity of the enzyme system

　　3.1 of fluoride on adenylate cyclase affect Fassina, etc. (1972) [10] studies have reported that fluoride into the body, increase or inhibit the cell membrane adenylate cyclase (AC) activity, the intracellular cyclic AMP (cAMP) levels increased or reduced, thus affecting the formation of ATP. cAMP as a second messenger of thyroid hormone, the normal functioning of thyroid hormone plays an important regulatory role. increase or decrease cAMP, directly affect thyroid function.

　　3.2 fluoride on Na + , K + -ATP effects Ballantyne, etc. (1981) [11] reported that fluoride can inhibit the cell membrane Na + , K + -ATP enzyme activity. Iodine from the blood transported to the basal membrane of thyroid is an active transport process, the need to consume large amounts of energy. In the bottom of the thyroid follicular cells are dependent on the cell membrane Na + , K + -ATP enzyme iodine pump during transit in iodine plays a key role: its promotion of iodine into the thyroid follicular epithelium and prevent follicular iodine within the outflow and enhance polyiodides effect. Excessive fluoride, Na + , K + -ATP enzyme inhibition, hinder the normal transit of iodine, thus affecting the synthesis and secretion of thyroid hormones. In addition, thyroid hormone is organized by directly stimulating the cell membrane sodium pump to complete thermogenic effect, this effect of normal play but also with Na + , K + -ATP enzyme closely related. Fluoride inhibits Na + , K + -ATP enzyme activity, resulting in heat production of thyroid hormone suppression.

　　3.3 of fluoride on thyroid proteolytic enzymes thyroglobulin (TG) is a huge globular glycoprotein molecules, shouldering a dual role: as iodinated tyrosine and thyroid hormone synthesis carrier; Second, iodine and storage the synthesis of thyroid hormones. TG synthesis stored in the follicular cavity, using time, TG were re-absorbed into the follicular epithelial cells, the formation of colloidal droplets, colloidal time digested by protease, the release of T 4 , T 3 and diiodo tyrosine acid (DIT) and an iodine tyrosine (MIT). Willems (1972) study shows that fluoride inhibits promote TG decomposed into T 3 , T 4 protease activity [12,13] . TG hydrolysis fluoride protease inhibition activity, resulting in reduced TG decomposition, with the TG on T 3 , T 4 , DIT, MIT not be freed, thus affecting the release of thyroid hormones and recycling iodine.

　　3.4 fluoride effects on thyroid peroxidase Data reported, excess fluoride can inhibit thyroid peroxidase (TPO) activity [14] . TPO is a hemoglobin iron porphyrin substances, the main biological role is to activate iodine, iodide, and the promotion of iodinated tyrosine tyrosine coupling, in the synthesis of thyroid hormone plays a key effect. Fluoride inhibition of the activity of TPO, the multiple aspects of thyroid hormone synthesis inhibition, causing thyroid hormone synthesis disorders.

　　4 fluorine interference carbohydrate and lipid metabolism in the thyroid cell theory

　　Shashi, etc. (1988) Experimental studies have shown that with rabbit [15] , fluorine poisoning rabbits, rabbits have a lot of fat accumulation in the thyroid gland, there hyperlipidemia, thyroid lipids, total lipid and triglyceride levels abnormal increase , the free fatty acid content was significantly reduced. Fluorine is a potential inhibitor of anaerobic glycolysis. Oxide also interfere with glucose decomposition system, leading to accumulation of DPG and ATP synthesis decreased [16] . Because thyroid cells carbohydrate, lipid metabolism disorders, will inevitably affect the thyroid hormone synthesis, secretion, affecting thyroid function.

　　In short, the above reasoning and assumptions are correct, need further proof. Reveals fluoride toxicological mechanisms of thyroid damage the arduous task of the future.

　　About the author: Chai Chunyan Review

　　Kang Shiliang revisers

　　Author: Northeast Agricultural University, Harbin 150030

　　References

　　[1] IRPTC.Scientific reviews of soviet literature on toxicity and hazards of chemicals, sodium fluoride [M]. United Nations environment programme, 38.Moscow: Centre of international projects GKNT ,1983:5-35.

　　[2] Hillman D.Hypothyroidism and anemia related to fluoride in dairy cattle [J]. Dairy Science ,1979,62:416-423.

　　[3] Juvenal GJ.Role of neurotransmitters, prostoglandins and glcose on precursor incorporation into the RNA of thyroid slices [J]. Acta Endocrinologica, 1978; 87:776-785.

　　[4] Largent EJ.Fluorine and compounds luigi parmeggiani.Encyclopaedia of occupational health and safety [M]. Third (Revised) Edition.Switzland: ILO Geneva ,1983:891-894.

　　[5] Editorial.Hydrogen bonding by fluoride ion: Mechannism of toxicity [J]. Fluoride, 1982,15 (2): 98.

　　[6] Li Jian science, Zhang Yanming, Zhang Gao. Fluorine and hydrogen bonding interactions tyrosine phenolic hydroxyl group into a quantum mechanical calculations [J]. Endemic Disease Bulletin .1991,6 (1) :11-14.

　　[7] Wang Huizhong Organic Chemistry and reagents [M]. Beijing: China Construction Workers Press .1987,168.

　　[8] Wu Nanping, ZHAO Zhong-liang, Gao Wenhua. Fluoride on developing the role of lipid peroxidation effects [J]. Fluoride Research Communications, 1993,8 (1): 27.

　　[9] Jeji.Implication of glutathione inendemic fluorosis [J]. Fluoride, 1985,18 (2): 117.

　　[10] Fassina G.Effects of glycolysis inhibitors on cyclic AMP synthesis in rat adipose tissue [J]. Biochem.Pharmacol ,1972,21:2295-2301.

　　[11] Ballantyne DJ.Chloroplast electron transport protein and RNA in fluoride treated shoots [J]. Environ Expere Botany ,1981,21:83-88.

　　[12] Willems C.Inhibition of thyroid secretion by sodium fluoride in vitro [J]. Biochem Biophys Acta ,1972,264:197-204.

　　[13] Bobek S.Effect of long term fluoride administration on thyroid Hormones level in blood in rats [J]. Endocrinol Exp ,1976,10:289-295.

　　[14] Xu Deshun, Xuguang Tao. Fluoride effects on thyroid [J]. Foreign Medical Medgeography, 1984,5 (1) :1-5.

　　[15] ShaShi.Biochemical effects of fluoride on thyroid gland during experimental fluorosis [J]. Fluoride, 1988,21 (3) :127-130.

　　[16] Dirksen TR.In vitro effects of fluoride on lipid synthesis by rat calvaria [J]. Arch Oral Biol ,1972,17:55-59.