鸡矢藤提取物对实验性高尿酸血症的影响
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摘要
高尿酸血症(Hyperuricemia)是由于嘌呤代谢紊乱致尿酸生成增多或因肾脏排泄障碍而引发,与痛风发病高度相关,是产生痛风性关节炎和尿酸性肾脏损害的重要生化基础。鸡矢藤提取物(Extracts of Paederia Scandens,EPS)是从茜草科鸡矢藤属植物鸡矢藤中提取的一类有效成分,其主要活性成份为鸡矢藤苷、鸡矢藤次苷、车叶草苷、r-谷甾醇及挥发油等。现代中医理论认为,鸡矢藤性平、味甘、微苦,具有祛风利湿、消炎止痛等多种功效。但有关EPS对高尿酸血症的作用尚未见报道。本课题主要研究EPS对实验性高尿酸血症的影响并对其作用机制进行了初步探讨。主要实验结果如下:
1 EPS对正常小鼠的影响
结果显示,EPS(6.30、3.15、1.57 g/kg,ig,qd×14d)对正常小鼠血清尿酸水平及肝脏黄嘌呤氧化酶(Xanthien oxidase,XO)的活性无明显影响,对小鼠的体重也无明显影响。
2 EPS对酵母膏致小鼠高尿酸血症的影响
选用酵母膏(30 g/kg,ig,qd×14d)为造模试剂制备小鼠高尿酸血症模型。结果显示,EPS(6.30、3.15、1.57 g/kg,ig,qd×14d)可显著降低酵母膏致高尿酸血症小鼠的血清尿酸水平并使其恢复至正常水平,且可明显抑制高尿酸血症小鼠肝脏XO的活性。提示EPS的降尿酸作用可能与其抑制XO的活性有关。
3 EPS对酵母膏和氧嗪酸钾致小鼠高尿酸血症的影响
选用酵母膏(30 g/kg,ig,qd×14d)和氧嗪酸钾(300 mg/kg,ip,14~(th),qd)为造模试制备小鼠高尿酸血症模型。结果显示,EPS(6.30、3.15、1.57 g/kg,ig,qd×14d)可显著降低酵母膏和氧嗪酸钾致高尿酸血症小鼠的血清尿酸水平,明显抑制模型小鼠的肝脏XO活性,对小鼠的体重及血清肌酐和尿素氮含量无明显影响;EPS(6.30g/kg,ig,qd×14d)可降低模型小鼠的血清腺苷脱氨酶(Adenosine deaminase,ADA)活性。提示EPS的降尿酸作用与其抑制肝脏XO的活性及降低血清中的ADA活性有关,同时也说明鸡矢藤提取物具有较高的安全性。
4 EPS对氧嗪酸钾致大鼠高尿酸血症的影响
选用氧嗪酸钾(200 mg/kg,ip,14~(th),qd)为造模试剂制备大鼠高尿酸血症模型。结果表明,EPS(4.50、2.25、1.125 g/kg,ig,qd×14d)均可明显降低高尿酸血症大鼠的血清尿酸水平,显著抑制模型大鼠肝脏XO活性,对大鼠血清和肝脏的ADA活性无明显改变;EPS(4.50、2.25 g/kg,ig,qd×14d)可显著提高高尿酸血症大鼠尿酸分级排泄。提示EPS的降尿酸作用可能主要通过促进尿酸排泄和抑制XO活性两条途径实现的。
5 EPS在体外对XO活性的影响
EPS体外实验结果显示,EPS(1.60、0.80、0.40 g/L)可以抑制XO活性,Lineweaver-Burk作图可以看出EPS对XO的抑制呈混合型抑制作用。提示EPS的降尿酸作用很可能与其抑制XO的活性有关,IC_(50)为1.00 g/L。
结论:EPS对高尿酸血症动物模型具有明显的降尿酸作用,其机制可能与抑制黄嘌呤氧化酶活性以及促进尿酸排泄有关。
Hyperuricemia is a metabolic disorder associated with abnormal amounts of uric acid in the body caused by overproduction or low excretion,resulting in gouty arthritis and uric acid nephrolithiasis.Extracts from Paederia Scandens(EPS) was extracted from Paederia scandens(Lour.) Merrill.The essential components of EPS are asperuloside, paederoside,scandoside,γ-sitosterol,essential oil et al.Paederia scandens was described to use as analgesic,anti-inflammatory,and to treat bruise and rheumatism through eliminating heat and excreting dampness in terms of traditional Chinese medicine.It has not been reported about the hypouricemic effect of EPS.This study is intended to investigate the hypouricemic effect of EPS.The main results are as follow:
1 Effects of EPS on normal mice
EPS(6.30,3.15,1.57 g/kg,ig,qd×14d) had no significant effects on serum uric acid level,the XO activity and the body weight of normal mice.
2 Effects of EPS on hyperurieemie mouse induced by yeast
The experimental animal model of hyperuricemia induced by i.g.of yeast(30 g/kg,ig, qd×14d) was adopted.The results showed that,EPS(6.30,3.15,1.57 g/kg,ig,qd×14d) could reduce serum uric acid level to the normal,and decrease in the xanthine oxidase activity in the mouse liver was significantly.These findings indicate that EPS could effectively inhibit the xanthine oxidase activity and show hypouricemic effect.
3 Effects of EPS on hyperuricemic mouse induced by yeast and potassium oxonate
The experimental animal model of hyperuricemia induced by i.g.of yeast(30 g/kg,ig, qd×14d) and i.p.of potassium oxonate(300 mg/kg,ip,14~(th),qd) was adopted.The results showed that,EPS(6.30,3.15,1.57 g/kg,ig,qd×14d) could reduce serum uric acid level,and decrease in the xanthine oxidase activity in the mouse liver was obvioustly.EPS(6.30,3.15,1.57 g/kg,qd×14d) had no effct on body weight,serum Cre and BUN.EPS(6.30 g/kg,qd×14d) could reduce the ADA activity.These findings indicate that the hypouricemic effect of EPS may be caused by inhibition of XO and ADA activity.And EPS can be used safely.
4 Effects of EPS on hyperuricemic rat induced by potassium oxonate
The experimental animal model of hyperuricemia induced by i.p.of potassium oxonate (200 mg/kg,ip,14~(th),qd) was adopted.The results showed that,EPS(4.50,2.25,1.125 g/kg,ig,qd×14d) could reduce serum uric acid level,and decrease in the xanthine oxidase activity in the mouse liver was significantly.EPS(4.50,2.25,1.125 g/kg,ig,qd×14d) had no effct on serum and liver ADA activity.EPS(4.50,2.25 g/kg,ig,qd×14d) could obviously increase the fractional excretion of urate in the hyperuricemic rats. These results suggest that the hypouricemic effect is partly due to inhibition of XO activity in rat liver and enhancement urate clearance.
5 Inhibitory activities of EPS on xanthine oxidase in vitro
The results showed that,EPS(1.60,0.80,0.40 g/L) could decrease the activity of XO. Lineweaver-burk analysis of the enzyme kinetics data showed that the inhibition of xanthine oxidase by EPS was of a mixed type.These results suggest EPS can inhibit the activity of xanthine oxidase in a concentration-dependent manner,with an IC_(50) value of 1.00 g/L.
Conclusion:EPS exhibited hyporuicemic effect on hyperuricemia model animals,and its mechanisms might be associated with inhibition of XO activity and enhancement of urate clearance.
1 EPS对正常小鼠的影响
结果显示,EPS(6.30、3.15、1.57 g/kg,ig,qd×14d)对正常小鼠血清尿酸水平及肝脏黄嘌呤氧化酶(Xanthien oxidase,XO)的活性无明显影响,对小鼠的体重也无明显影响。
2 EPS对酵母膏致小鼠高尿酸血症的影响
选用酵母膏(30 g/kg,ig,qd×14d)为造模试剂制备小鼠高尿酸血症模型。结果显示,EPS(6.30、3.15、1.57 g/kg,ig,qd×14d)可显著降低酵母膏致高尿酸血症小鼠的血清尿酸水平并使其恢复至正常水平,且可明显抑制高尿酸血症小鼠肝脏XO的活性。提示EPS的降尿酸作用可能与其抑制XO的活性有关。
3 EPS对酵母膏和氧嗪酸钾致小鼠高尿酸血症的影响
选用酵母膏(30 g/kg,ig,qd×14d)和氧嗪酸钾(300 mg/kg,ip,14~(th),qd)为造模试制备小鼠高尿酸血症模型。结果显示,EPS(6.30、3.15、1.57 g/kg,ig,qd×14d)可显著降低酵母膏和氧嗪酸钾致高尿酸血症小鼠的血清尿酸水平,明显抑制模型小鼠的肝脏XO活性,对小鼠的体重及血清肌酐和尿素氮含量无明显影响;EPS(6.30g/kg,ig,qd×14d)可降低模型小鼠的血清腺苷脱氨酶(Adenosine deaminase,ADA)活性。提示EPS的降尿酸作用与其抑制肝脏XO的活性及降低血清中的ADA活性有关,同时也说明鸡矢藤提取物具有较高的安全性。
4 EPS对氧嗪酸钾致大鼠高尿酸血症的影响
选用氧嗪酸钾(200 mg/kg,ip,14~(th),qd)为造模试剂制备大鼠高尿酸血症模型。结果表明,EPS(4.50、2.25、1.125 g/kg,ig,qd×14d)均可明显降低高尿酸血症大鼠的血清尿酸水平,显著抑制模型大鼠肝脏XO活性,对大鼠血清和肝脏的ADA活性无明显改变;EPS(4.50、2.25 g/kg,ig,qd×14d)可显著提高高尿酸血症大鼠尿酸分级排泄。提示EPS的降尿酸作用可能主要通过促进尿酸排泄和抑制XO活性两条途径实现的。
5 EPS在体外对XO活性的影响
EPS体外实验结果显示,EPS(1.60、0.80、0.40 g/L)可以抑制XO活性,Lineweaver-Burk作图可以看出EPS对XO的抑制呈混合型抑制作用。提示EPS的降尿酸作用很可能与其抑制XO的活性有关,IC_(50)为1.00 g/L。
结论:EPS对高尿酸血症动物模型具有明显的降尿酸作用,其机制可能与抑制黄嘌呤氧化酶活性以及促进尿酸排泄有关。
Hyperuricemia is a metabolic disorder associated with abnormal amounts of uric acid in the body caused by overproduction or low excretion,resulting in gouty arthritis and uric acid nephrolithiasis.Extracts from Paederia Scandens(EPS) was extracted from Paederia scandens(Lour.) Merrill.The essential components of EPS are asperuloside, paederoside,scandoside,γ-sitosterol,essential oil et al.Paederia scandens was described to use as analgesic,anti-inflammatory,and to treat bruise and rheumatism through eliminating heat and excreting dampness in terms of traditional Chinese medicine.It has not been reported about the hypouricemic effect of EPS.This study is intended to investigate the hypouricemic effect of EPS.The main results are as follow:
1 Effects of EPS on normal mice
EPS(6.30,3.15,1.57 g/kg,ig,qd×14d) had no significant effects on serum uric acid level,the XO activity and the body weight of normal mice.
2 Effects of EPS on hyperurieemie mouse induced by yeast
The experimental animal model of hyperuricemia induced by i.g.of yeast(30 g/kg,ig, qd×14d) was adopted.The results showed that,EPS(6.30,3.15,1.57 g/kg,ig,qd×14d) could reduce serum uric acid level to the normal,and decrease in the xanthine oxidase activity in the mouse liver was significantly.These findings indicate that EPS could effectively inhibit the xanthine oxidase activity and show hypouricemic effect.
3 Effects of EPS on hyperuricemic mouse induced by yeast and potassium oxonate
The experimental animal model of hyperuricemia induced by i.g.of yeast(30 g/kg,ig, qd×14d) and i.p.of potassium oxonate(300 mg/kg,ip,14~(th),qd) was adopted.The results showed that,EPS(6.30,3.15,1.57 g/kg,ig,qd×14d) could reduce serum uric acid level,and decrease in the xanthine oxidase activity in the mouse liver was obvioustly.EPS(6.30,3.15,1.57 g/kg,qd×14d) had no effct on body weight,serum Cre and BUN.EPS(6.30 g/kg,qd×14d) could reduce the ADA activity.These findings indicate that the hypouricemic effect of EPS may be caused by inhibition of XO and ADA activity.And EPS can be used safely.
4 Effects of EPS on hyperuricemic rat induced by potassium oxonate
The experimental animal model of hyperuricemia induced by i.p.of potassium oxonate (200 mg/kg,ip,14~(th),qd) was adopted.The results showed that,EPS(4.50,2.25,1.125 g/kg,ig,qd×14d) could reduce serum uric acid level,and decrease in the xanthine oxidase activity in the mouse liver was significantly.EPS(4.50,2.25,1.125 g/kg,ig,qd×14d) had no effct on serum and liver ADA activity.EPS(4.50,2.25 g/kg,ig,qd×14d) could obviously increase the fractional excretion of urate in the hyperuricemic rats. These results suggest that the hypouricemic effect is partly due to inhibition of XO activity in rat liver and enhancement urate clearance.
5 Inhibitory activities of EPS on xanthine oxidase in vitro
The results showed that,EPS(1.60,0.80,0.40 g/L) could decrease the activity of XO. Lineweaver-burk analysis of the enzyme kinetics data showed that the inhibition of xanthine oxidase by EPS was of a mixed type.These results suggest EPS can inhibit the activity of xanthine oxidase in a concentration-dependent manner,with an IC_(50) value of 1.00 g/L.
Conclusion:EPS exhibited hyporuicemic effect on hyperuricemia model animals,and its mechanisms might be associated with inhibition of XO activity and enhancement of urate clearance.
引文
1.Omita M,Mizuno S,Yamanaka H,et al.Does hyperuricemia affect mortality:a prospective cohort study of Japanese male workers? J Epidemiol,2000,10:403.
2.Maxxali M,Hughes J,Kim YG,et al.Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.Hypertension.2001,38:1101.
3.吴炜戒,郭阶明,杨薇,等.广州市1482例体检人员痛风和高尿酸血症患病现状的调查.海南医学,2007,18(9):110.
4.苗志敏,赵世华,王颜刚,等.山东沿海居民高尿酸血症及痛风的流行病学调查.中华内分泌代谢杂志,2006,22(5):421.
5.李红,张明轩,肖静.河南省中老年干部高尿酸血症患病情况调查.郑州大学学(医学版),2002,37(1):87.
6.吴云娟.别嘌醇致再生障碍性贫血.药物不良反应杂志,2002,6(3):67.
7.尚雁君,郭跃伟,黄才国,等.中国南海海绵提取物renierol对黄嘌呤氧化酶的抑制作用.第二军医大学学报,2006,27(1):25.
8.尚雁君,李医明,蒋山好,等.玄参中苯丙素苷Acteoside对小鼠高尿酸血症的影响.解放军药学学报.2006,22(1):30.
9.Kong LD,Yang C,Ge F,et al.A Chinese herbal medicine Ermiao wan reduces serum uric acid level and inhibits liver xanthine dehydrogenase and xanthine oxidase in mice.J Ethnopharmacol,2004,93(2-3):325.
10.Wang Y,Zhu JX,Kong LD,et al.Administration of procyanidins from grape seeds reduces serum uric acid levels and decreases hepatic xanthine dehydrogenase/oxidase activities in oxonate-treated mice.Basic Clin Pharmacol Toxicol,2004,94(5):232.
11.Zhu JX,Wang Y,Kong LD,et al.Effects of Biota orientalis extract and its flavonoid constituents,quercetin and rutin o serum uric acid levels in oxonate-induced mice and xanthine dehydrogenase and xanthine oxidase activities in mouse liver.J Ethnopharmacol,2004;93(1):133.
12.Arroll JJ,Roberta Douglass HC,Babson AL.A simplified alkaline phosphotungstate assay for uric acid in serum.Clin.Chem.1971;17(3):158.
13.Kong LD,Zhou J,Wen YL,et al.Aesculin possesses potent hypouricemic action in rodents but is devoid of xanthine oxidase/dehydrogenase inhibitory activity.Planta Med.2002;68(2):175.
14.Dan T,Yoneya T,Onuma E et al.Hypouricemic and uricosuric actions of AA-193in a hyperuricemic rat model.Metabolism.1994,43:123.
15.付海英,洪敏,高琳等.吗啡对大鼠肝脏蛋白质及核酸分解代谢关键酶基因表达的影响.吉林大学学报(医学版),2004,30(6):878.
16.阚慕洁,洪敏,周宏等.吗啡对大鼠嘌呤核苷酸分解代谢的促进作用及其可能的作用机制.中国药理学通报,2004,20(3):311.
17.孟昭亨编著.痛风.北京:北京医科大学出版社中国医科大学联合出版社.1997,62.
18.曹克光,威力学.高尿酸血症动物模型的建立及应用.实验动物科学与管理,2000,2(6):6.
19.刘小青,张冰,刘春梅等.鹌鹑高尿酸血症模型建立初探.中国病理生理杂志,2001,17(10):1038.
20.Wu X,Wakamiya M,Vaishnav S,et al.Hyperuricemia and urate nephropathy in urate oxidase-deficient mice.Proe Natl Acad Sci USA.1994;91(2):742.
21.Fridovich I.The competitive inhibition of uricase by ononate and by related derivatives of s-triazines.J.Biol.Chem.1965;240:2491.
22.Johnson WJ,Stavric B,Chartrand A.Uricase inhibition in the rat by s-triazines:an animal model for hyperuricemia and hyperuricosuria.Proc.Soc.Exptl.Biol.Med, 1969;131(1):8.
23.Iris HH,John PS,Dvid JR,et al.Substituted cyclic imides as potential anti-gout agents.Life sciense.1990;46(26):1923.
24.Kazumi I,Yukio Y.Hyperuricemic effects of cholinergic agents in rats.Japan.J.Pharmcol.1982;32:343.
25.喻志峰,杨澄,仇熙,等.瑞香苷对高尿酸血症小鼠的影响.中国药科大学学报,2002,33(2):142.
26.王海东,葛飞,郭玉松,等.金钱草提取物对高尿酸血症小鼠的影响.中国中药杂志,2002,27(12):939.
27.Staviriv B,Clayman S,Gradd REA.Some in vivo effects in the rat induced by chlorprothixene and potassium oxonate.Pharm Res Comm.1975;117.
28.Ferrand G,Dumas H,Decerprit J.Synthesis of new pteridines as hyporuicemia is agents.Ear J Med Chem.1992;27:209.
29.陈光亮,孙秀霞,王钦茂,等.小鼠高尿酸血症模型的研究.中国药理学通报,2001,17(3):350.
30.金沈锐,郑军,刘绍唐.小鼠高尿酸血症模型初探.成都中医药大学学报,1999;22(1):49.
31.唐灿,杨奎.高尿酸血症动物模型初探.中药新药与临床药理,2000,11(5):292.
32.熊湘明,曲竹秋.大鼠高尿酸血症模型建立.天津中医学院学报,2001,20(4):28.
33.陈光亮,张清林,马晓芹,等.酵母膏致小鼠高尿酸血症模型.中国药理学通报,2003,19(4):467.
34.张冰,刘小青,丁正磊,等.鹌鹑高尿酸血症模型发病机理研究.北京中医药大学学报,2006,29(9):595.
35.王诗瑾,张喑,钱书红等.四唑盐比色法测定血清黄嘌呤氧化酶.河南医科大学学报.1993,28(3):277
36.Levinson DJ and Sorensen LB.Renal handling of uric acid in normal and gouty subject:evidence for a 4-component system.Ann Rheum Dis.1980;39(2):173.
37. Weiner IM. Urate transport in the nephron. Am J Physiol. 1979; 237(2): 85.
38. Holmes K and Kelley WN. Absence of significant urate binding to human serum proteins. J Lab Clin Med. 1979; 93(1): 85.
39. Cha S and Endou H. The multispecific organic anion transporter (OAT) family.Pflugers Arch. 2000; 440(3): 337.
40. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002; 417(6887):447.
1.Johnson RJ,Kang DH,Feig D,et al.Is there a pathogenic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41(6):1183.
2.Sekine T,Watanabe N,Hosoyamada M,et al.Expression.cloning and characterization of a novel multispecific organic anion transporter.J Biol Chem 1997;272(30):18526.
3.Enomoto A,Kimura H,Chairoungdua A,et al.Molecular identification of a renal urate anion exchanger that regulates blood urate levels.Nature 2002;417(6887):447.
4.吴镝,张萍,陈香美,等.人肾尿酸转运蛋白1基因克隆、抗体制备及其在肾小管上皮细胞中的定位.解放军医学杂志,2005,30(5):397.
5.洪权,吴镝,陈香美,等.尿酸转运蛋白在肾小管上皮细胞的定位表达研究.中华肾脏病杂志,2005,21(9):527.
6.Diamond HS.Interpretation of pharmacologic manipulation of urate transport in man.Nephron 1989;51(1):1.
7.Maesaka JK,Fishbane S.Regulation of renal urate excretion a critical review.Am J Kidney Dis,1998,32(6):917.
8.Levinson DJ and Sorensen LB.Renal handling of uric acid in normal and gouty subject:evidence for a 4-component system.Ann Rheum Dis.1980;39(2):173.
9.Weiner IM.Urate transport in the nephron.Am J Physiol.1979;237(2):85.
10.Sica DA,Schoolwerth AC.Renal handling of organic anions and cations:Excretion of uric acid.In:Brenner BM,editor.The kidney[M].6th ed.Philadelphia:WB Saunders;2000.p.680.
11.Abramson RG,Lipkowitz MS.Evolution of the uric acid transport mechanisms in vertebrate kidney.In:Kinne RKH,editor.Basic principles in transport[M].Comparative Physiology,Vol.3.Basel:Karger,1990.p.115.
12.Dantzler WH.Comparative aspects of renal urate transport.Kidney Int 1996;49(6):1549.
13.Enomoto A,Endou H.Roles of organic anion transporters(OATs) and a urate transporter(URAT1) in the pathophysiology of human disease.Clin Exp Nephrol 2005;9(3):195.
14.Geri L,Youngblood,Sweet DH.Identification and functional assessment of the novel murineorganic anion transporter Oat5(S1c22al 9) expressed in kidney.Am J Physiol Renal Physiol.2004,287(2):236.
15.Cheong HI,Kang JH,Lee JH,et al.Mutational analysis of idiopathic renal hypouricemia in Korea.Pediatr Nephrol 2005.20(7):886.
16. Hosoyamada M, Sekine T, Kanai Y, et al. Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol 1999; 276(1): 122.
17. Race JE, Grassl SM, Williams WJ, et al. Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT 1 and hOAT 3). Biochem Biophys Res Commun 1999; 255(2): 508.
18. Ichida K, Hosoyamada M, Hisatome I, Enomoto A, et al. Clinical and molecular analysis of patients with renal hypouricemia in Japan—influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004; 15(1):164.
19. Coady MJ, Chang MH, Charron FM, et al. The human tumour suppressor gene SLC5A8 expresses a Na-monocarboxylate cotransporter. J Physiol. 2004;557(3):719.
20. Gopal E,Fei YJ,Sugawama M, et al. Expression of slc5a8 in kidney and its role in Na (+)-coupled transport of lactate. J Biol Chem. 2004; 279(43):44522.
21. Guggino SE and Aronson PS. Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes. J Clin Invest 1985; 76(2):543.
22. Weiner IM and Tinker JP. Pharmacology of pyrazinamide: metabolic and renal function studies related to the mechanism of drug-induced urate retention. J Pharmacol Exp Ther 1972; 180(2): 411.
23. Roch-Ramel FB and Schild L. Indirect coupling of urate and p-aminohippurate transport to sodium in human brush-border membrane vesicles. Am J Physiol 1996;270(1): 61.
24. Guggino SE, Martin GJ and Aronson PS. Specificity and modes of the anion exchanger in dog renal microvillus membranes. Am J Physiol 1983; 244(6): 612.
25. Sekine T, Cha SH, Endou H. The multispecific organic anion transporter (OAT) family. Pflugers Arch - Eur J Physiol .2000; 440(3):337.
26. You G, Kuze K, Kohanski RA, et al. Regulation of mOAT-mediated organic anion transport by okadaic acid and protein kinase C in LLC-PK1 cells. J Biol Chem 2000;275(14): 10278.
27. Sauvant C, Holzinger H, Gekle M. Modulation of the basolateral and apical step of transepithelial organic anion secretion in proximal tubular opossum kidney cells. J Biol Chem 2001; 276(18): 14695.
28. Anzai N, Miyazaki H, Noshiro R, et al. The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C-terminal. J Biol Chem 2004; 279(44):45942.
29. Wang S, Yue H, Derin RB, et al. Accessory protein facilitated CFTR-CFTR interaction: a molecular mechanism to potentiate the chloride channel activity. Cell 2000; 103(1):169.
30. Gisler SM, Pribanic S, Bacic D, et al .PDZK1- A major scaffolder in brush borders of proximal tubular cells. Kidney Int 2003; 64(5):1733.
31. Hosoyamada M, Ichida K, Enomoto A, et al. Function and localization of urate transporter 1 in mouse kidney. J Am Soc Nephrol 2004; 15(2):261.
2.Maxxali M,Hughes J,Kim YG,et al.Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.Hypertension.2001,38:1101.
3.吴炜戒,郭阶明,杨薇,等.广州市1482例体检人员痛风和高尿酸血症患病现状的调查.海南医学,2007,18(9):110.
4.苗志敏,赵世华,王颜刚,等.山东沿海居民高尿酸血症及痛风的流行病学调查.中华内分泌代谢杂志,2006,22(5):421.
5.李红,张明轩,肖静.河南省中老年干部高尿酸血症患病情况调查.郑州大学学(医学版),2002,37(1):87.
6.吴云娟.别嘌醇致再生障碍性贫血.药物不良反应杂志,2002,6(3):67.
7.尚雁君,郭跃伟,黄才国,等.中国南海海绵提取物renierol对黄嘌呤氧化酶的抑制作用.第二军医大学学报,2006,27(1):25.
8.尚雁君,李医明,蒋山好,等.玄参中苯丙素苷Acteoside对小鼠高尿酸血症的影响.解放军药学学报.2006,22(1):30.
9.Kong LD,Yang C,Ge F,et al.A Chinese herbal medicine Ermiao wan reduces serum uric acid level and inhibits liver xanthine dehydrogenase and xanthine oxidase in mice.J Ethnopharmacol,2004,93(2-3):325.
10.Wang Y,Zhu JX,Kong LD,et al.Administration of procyanidins from grape seeds reduces serum uric acid levels and decreases hepatic xanthine dehydrogenase/oxidase activities in oxonate-treated mice.Basic Clin Pharmacol Toxicol,2004,94(5):232.
11.Zhu JX,Wang Y,Kong LD,et al.Effects of Biota orientalis extract and its flavonoid constituents,quercetin and rutin o serum uric acid levels in oxonate-induced mice and xanthine dehydrogenase and xanthine oxidase activities in mouse liver.J Ethnopharmacol,2004;93(1):133.
12.Arroll JJ,Roberta Douglass HC,Babson AL.A simplified alkaline phosphotungstate assay for uric acid in serum.Clin.Chem.1971;17(3):158.
13.Kong LD,Zhou J,Wen YL,et al.Aesculin possesses potent hypouricemic action in rodents but is devoid of xanthine oxidase/dehydrogenase inhibitory activity.Planta Med.2002;68(2):175.
14.Dan T,Yoneya T,Onuma E et al.Hypouricemic and uricosuric actions of AA-193in a hyperuricemic rat model.Metabolism.1994,43:123.
15.付海英,洪敏,高琳等.吗啡对大鼠肝脏蛋白质及核酸分解代谢关键酶基因表达的影响.吉林大学学报(医学版),2004,30(6):878.
16.阚慕洁,洪敏,周宏等.吗啡对大鼠嘌呤核苷酸分解代谢的促进作用及其可能的作用机制.中国药理学通报,2004,20(3):311.
17.孟昭亨编著.痛风.北京:北京医科大学出版社中国医科大学联合出版社.1997,62.
18.曹克光,威力学.高尿酸血症动物模型的建立及应用.实验动物科学与管理,2000,2(6):6.
19.刘小青,张冰,刘春梅等.鹌鹑高尿酸血症模型建立初探.中国病理生理杂志,2001,17(10):1038.
20.Wu X,Wakamiya M,Vaishnav S,et al.Hyperuricemia and urate nephropathy in urate oxidase-deficient mice.Proe Natl Acad Sci USA.1994;91(2):742.
21.Fridovich I.The competitive inhibition of uricase by ononate and by related derivatives of s-triazines.J.Biol.Chem.1965;240:2491.
22.Johnson WJ,Stavric B,Chartrand A.Uricase inhibition in the rat by s-triazines:an animal model for hyperuricemia and hyperuricosuria.Proc.Soc.Exptl.Biol.Med, 1969;131(1):8.
23.Iris HH,John PS,Dvid JR,et al.Substituted cyclic imides as potential anti-gout agents.Life sciense.1990;46(26):1923.
24.Kazumi I,Yukio Y.Hyperuricemic effects of cholinergic agents in rats.Japan.J.Pharmcol.1982;32:343.
25.喻志峰,杨澄,仇熙,等.瑞香苷对高尿酸血症小鼠的影响.中国药科大学学报,2002,33(2):142.
26.王海东,葛飞,郭玉松,等.金钱草提取物对高尿酸血症小鼠的影响.中国中药杂志,2002,27(12):939.
27.Staviriv B,Clayman S,Gradd REA.Some in vivo effects in the rat induced by chlorprothixene and potassium oxonate.Pharm Res Comm.1975;117.
28.Ferrand G,Dumas H,Decerprit J.Synthesis of new pteridines as hyporuicemia is agents.Ear J Med Chem.1992;27:209.
29.陈光亮,孙秀霞,王钦茂,等.小鼠高尿酸血症模型的研究.中国药理学通报,2001,17(3):350.
30.金沈锐,郑军,刘绍唐.小鼠高尿酸血症模型初探.成都中医药大学学报,1999;22(1):49.
31.唐灿,杨奎.高尿酸血症动物模型初探.中药新药与临床药理,2000,11(5):292.
32.熊湘明,曲竹秋.大鼠高尿酸血症模型建立.天津中医学院学报,2001,20(4):28.
33.陈光亮,张清林,马晓芹,等.酵母膏致小鼠高尿酸血症模型.中国药理学通报,2003,19(4):467.
34.张冰,刘小青,丁正磊,等.鹌鹑高尿酸血症模型发病机理研究.北京中医药大学学报,2006,29(9):595.
35.王诗瑾,张喑,钱书红等.四唑盐比色法测定血清黄嘌呤氧化酶.河南医科大学学报.1993,28(3):277
36.Levinson DJ and Sorensen LB.Renal handling of uric acid in normal and gouty subject:evidence for a 4-component system.Ann Rheum Dis.1980;39(2):173.
37. Weiner IM. Urate transport in the nephron. Am J Physiol. 1979; 237(2): 85.
38. Holmes K and Kelley WN. Absence of significant urate binding to human serum proteins. J Lab Clin Med. 1979; 93(1): 85.
39. Cha S and Endou H. The multispecific organic anion transporter (OAT) family.Pflugers Arch. 2000; 440(3): 337.
40. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002; 417(6887):447.
1.Johnson RJ,Kang DH,Feig D,et al.Is there a pathogenic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41(6):1183.
2.Sekine T,Watanabe N,Hosoyamada M,et al.Expression.cloning and characterization of a novel multispecific organic anion transporter.J Biol Chem 1997;272(30):18526.
3.Enomoto A,Kimura H,Chairoungdua A,et al.Molecular identification of a renal urate anion exchanger that regulates blood urate levels.Nature 2002;417(6887):447.
4.吴镝,张萍,陈香美,等.人肾尿酸转运蛋白1基因克隆、抗体制备及其在肾小管上皮细胞中的定位.解放军医学杂志,2005,30(5):397.
5.洪权,吴镝,陈香美,等.尿酸转运蛋白在肾小管上皮细胞的定位表达研究.中华肾脏病杂志,2005,21(9):527.
6.Diamond HS.Interpretation of pharmacologic manipulation of urate transport in man.Nephron 1989;51(1):1.
7.Maesaka JK,Fishbane S.Regulation of renal urate excretion a critical review.Am J Kidney Dis,1998,32(6):917.
8.Levinson DJ and Sorensen LB.Renal handling of uric acid in normal and gouty subject:evidence for a 4-component system.Ann Rheum Dis.1980;39(2):173.
9.Weiner IM.Urate transport in the nephron.Am J Physiol.1979;237(2):85.
10.Sica DA,Schoolwerth AC.Renal handling of organic anions and cations:Excretion of uric acid.In:Brenner BM,editor.The kidney[M].6th ed.Philadelphia:WB Saunders;2000.p.680.
11.Abramson RG,Lipkowitz MS.Evolution of the uric acid transport mechanisms in vertebrate kidney.In:Kinne RKH,editor.Basic principles in transport[M].Comparative Physiology,Vol.3.Basel:Karger,1990.p.115.
12.Dantzler WH.Comparative aspects of renal urate transport.Kidney Int 1996;49(6):1549.
13.Enomoto A,Endou H.Roles of organic anion transporters(OATs) and a urate transporter(URAT1) in the pathophysiology of human disease.Clin Exp Nephrol 2005;9(3):195.
14.Geri L,Youngblood,Sweet DH.Identification and functional assessment of the novel murineorganic anion transporter Oat5(S1c22al 9) expressed in kidney.Am J Physiol Renal Physiol.2004,287(2):236.
15.Cheong HI,Kang JH,Lee JH,et al.Mutational analysis of idiopathic renal hypouricemia in Korea.Pediatr Nephrol 2005.20(7):886.
16. Hosoyamada M, Sekine T, Kanai Y, et al. Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol 1999; 276(1): 122.
17. Race JE, Grassl SM, Williams WJ, et al. Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT 1 and hOAT 3). Biochem Biophys Res Commun 1999; 255(2): 508.
18. Ichida K, Hosoyamada M, Hisatome I, Enomoto A, et al. Clinical and molecular analysis of patients with renal hypouricemia in Japan—influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004; 15(1):164.
19. Coady MJ, Chang MH, Charron FM, et al. The human tumour suppressor gene SLC5A8 expresses a Na-monocarboxylate cotransporter. J Physiol. 2004;557(3):719.
20. Gopal E,Fei YJ,Sugawama M, et al. Expression of slc5a8 in kidney and its role in Na (+)-coupled transport of lactate. J Biol Chem. 2004; 279(43):44522.
21. Guggino SE and Aronson PS. Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes. J Clin Invest 1985; 76(2):543.
22. Weiner IM and Tinker JP. Pharmacology of pyrazinamide: metabolic and renal function studies related to the mechanism of drug-induced urate retention. J Pharmacol Exp Ther 1972; 180(2): 411.
23. Roch-Ramel FB and Schild L. Indirect coupling of urate and p-aminohippurate transport to sodium in human brush-border membrane vesicles. Am J Physiol 1996;270(1): 61.
24. Guggino SE, Martin GJ and Aronson PS. Specificity and modes of the anion exchanger in dog renal microvillus membranes. Am J Physiol 1983; 244(6): 612.
25. Sekine T, Cha SH, Endou H. The multispecific organic anion transporter (OAT) family. Pflugers Arch - Eur J Physiol .2000; 440(3):337.
26. You G, Kuze K, Kohanski RA, et al. Regulation of mOAT-mediated organic anion transport by okadaic acid and protein kinase C in LLC-PK1 cells. J Biol Chem 2000;275(14): 10278.
27. Sauvant C, Holzinger H, Gekle M. Modulation of the basolateral and apical step of transepithelial organic anion secretion in proximal tubular opossum kidney cells. J Biol Chem 2001; 276(18): 14695.
28. Anzai N, Miyazaki H, Noshiro R, et al. The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C-terminal. J Biol Chem 2004; 279(44):45942.
29. Wang S, Yue H, Derin RB, et al. Accessory protein facilitated CFTR-CFTR interaction: a molecular mechanism to potentiate the chloride channel activity. Cell 2000; 103(1):169.
30. Gisler SM, Pribanic S, Bacic D, et al .PDZK1- A major scaffolder in brush borders of proximal tubular cells. Kidney Int 2003; 64(5):1733.
31. Hosoyamada M, Ichida K, Enomoto A, et al. Function and localization of urate transporter 1 in mouse kidney. J Am Soc Nephrol 2004; 15(2):261.