臨床検査49巻2号

2005年02月発行

今月の主題 酸化ストレスマーカーと疾患・病態 話題

カルボキシメチルリジン

著者： 竹内正義¹

所属機関： ¹北陸大学薬学部病態生理化学教室

ページ範囲：P.197 - P.201

1. はじめに

　カルボキシメチルリジン〔N^ε-(carboxymethyl)lysine；CML〕は，1986年にAhmedらによりグルコースとリジンの反応産物の1つとして構造決定された¹⁾．In vitroにおけるCMLの主な生成経路はシッフ塩基あるいはアマドリ化合物の酸化的解裂によると考えられている．蛋白質中のCMLは酸加水分解に安定なこともあり，HPLC(high-performance liquid chromatography)法やGC/MS(gas chromatography/mass spectrometry)法で定量することが可能である．また，AGEs(advanced glycation end-products；終末糖化産物)化蛋白質中のCML部位は主要な抗体認識部位(エピトープ)であることが報告されたこともあり^2,3)，AGEsの定量は，構造が明らかになっているCMLの定量で代替されてきた．

　しかし近年，生体におけるCMLの主な供給源が脂質の過酸化であることが報告され⁴⁾，CMLはむしろ酸化ストレスのマーカーと考えられるに至っている．

　本稿では，CML研究の流れとCML測定の臨床的意義について概説するとともに，最近注目されているnon-CML AGEsの概念，なかでもTAGE(toxic AGEs)病因説について言及していく．

参考文献

１) Ahmed MU, Thorpe SR, Baynes JW：Identification of Nε-carboxymethyllysine as a degradation product of fructoselysine in glycated protein. J Biol Chem　261：4889-4894, 1986

２) Reddy S, Bichler J, Wells-Knecht KJ, et al：Nε-(Carboxymethyl) lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry　34：10872-10878, 1995

３) Ikeda K, Higashi T, Sano H, et al：Nε-(Carboxymethyl)lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. Biochemistry　35：8075-8083, 1996

４) Fu MX, Requena JR, Jenkins AJ, et al：The advanced glycation end product, Nε-(carboxymethyl) lysine, is a product of both lipid peroxidation and glycoxidation reactions. J Biol Chem　271：9982-9986, 1996

５) Glomb MA, Monnier VM：Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction. J Biol Chem　270：10017-10026, 1995

６) Wells-Knecht KJ, Zyzak DV, Litchfield JE, et al：Mechanism of autoxidative glycosylation：Identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. Biochemistry　34：3702-3709, 1995

７) Wells-Knecht MC, Lyons TJ, McCance DR, et al：Age-dependent increase in ortho-tyrosine and methionine sulfoxide in human skin collagen is not accelerated in diabetes：Evidence against a generalized increase in oxidative stress in diabetes. J Clin Invest　100：839-846, 1997

８) 中山秀隆：糖化蛋白の定量法．臨床検査　44：257-262, 2000

９) Nagai R, Ikeda K, Kawasaki Y, et al：Conversion of Amadori product of Maillard reaction to Nε-(carboxymethyl) lysine in alkaline condition. FEBS Lett　425：355-360, 1998

10) Miki Hayashi C, Nagai R, Miyazaki K, et al：Conversion of Amadori products of Maillard reaction to Nε-(carboxymethyl)lysine by short-term heating；possible detection of artifacts by immunohistochemistry. Lab Invest　82：795-808, 2002

11) Iwamoto H, Motomiya Y, Miura K, et al：Immunochemical assay of hemoglobin with Nε-(carboxymethyl)lysine at lysine 66 of the beta chain. Clin Chem　47：1249-1255, 2001

12) Motomiya Y, Iwamoto H, Uji Y, et al：Potential value of CML-Hb in predicting the progression of bone cysts in dialysis-related amyloidosis. Nephron　89：286-290, 2001

13) Miura J, Yamagishi S, Uchigata Y, et al：Serum levels of non-carboxymethyllysine advanced glycation endproducts are correlated to severity of microvascular complications in patients with type 1 diabetes. J Diabetes Complications　17：16-21, 2003

14) Takeuchi M, Makita Z, Yanagisawa K, et al：Detection of noncarboxymethyllysine and carboxymethyllysine advanced glycation end products in serum diabetic patients. Mol Med　5：393-405, 1999

15) Ahmed MU, Dunn JA, Walla MD, et al：Oxidative degradation of glucose adducts to protein. Formation of 3-(Nε-lysino)-lactic acid from model compounds and glycated proteins. J Biol Chem　263：8816-8821, 1988

16) Okamoto T, Yamagishi S, Inagaki Y, et al：Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. FASEB J　16：1928-1930, 2002

17) Yamagishi S, Inagaki Y, Okamoto T, et al：Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human cultured mesangial cells. J Biol Chem　277：20309-20315, 2002

18) Yamagishi S, Takeuchi M, Inagaki Y, et al：Role of advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy. Int J Clin Pharmacol Res　23：129-134, 2003

19) Takeuchi M, Yamagishi S：TAGE (toxic AGEs) hypothesis in various chronic diseases. Med Hypotheses　63：449-452, 2004

20) Takeuchi M, Yamagishi S：Alternative routes for the formation of glyceraldehyde-derived AGEs (TAGE) in vivo. Med Hypotheses　63：453-455, 2004

21) 竹内正義：AGEs研究の最前線(今泉勉監修)，メディカルレビュー社，pp27-36, 2004

22) 竹内正義：生活習慣病におけるTAGE(toxic AGEs)病因説，北陸大学 紀要　28：pp1-16, 2004