家永 和治 日本臓器製薬株式会社, 生物活性科学研究所, 部長
MAEDA Kenji Institution, Department of Internal Medicine, The Branch Hospital, Nagoya Univer, 医学部, 教授 (90023853)
IENAGA Kazuharu Institution, Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co.Ltd.
|Budget Amount *help
¥14,500,000 (Direct Cost : ¥14,500,000)
Fiscal Year 1996 : ¥5,100,000 (Direct Cost : ¥5,100,000)
Fiscal Year 1995 : ¥9,400,000 (Direct Cost : ¥9,400,000)
Incubation of glucose with proteins in vitro results in formation of early-products such as Schiff base and Amadori product. Upon further incubations, these early-products leads to formation of advanced glycation end products (AGE) which are characterized by fluorescence, brown color and intra-and intermolecular crosslinking. Recent immunological studies using anti-AGE antibody suggest a potential role of AGE-modification in aging and age-enhanced disease processes such as atherosclerosis and diabetic complications. To solve this suggestion, a main AGE-structure (s) expressed in vivo is to be determined. In the present study, we isolated the main AGE-structure from AGE-lysine derivative and determined its chemical structure.
The following results were obtained by two-years projects.
 The AGE-sample was obtained after long-term incubation of alpha-tosyl-lysine-methyl ester with glucose and the main fluorescent compound named as X1 was purified from this sample. Chemical analyzes by mass spectroscopy and 1H-NMR and 13C-NMR successfully identified its structure as 1,7-disubstituted-5- (1,2,3,4-tetrahydroxybutyl) -1,4-dihydro-4-oxo-1,7-naphthyridinium cation, indicating two lysine residues are crosslinked by pyridinium structure derived from two glucose molecules.
 Immunological studies using the rabbit polyclonal anti-X1 antibody demonstrated the presence of X1 in (i) human lens proteins, (ii) foam cells as well as in extracellular spaces in human atherosclerotic lesions, (iii) glomerulus and renal tubules of diabetic nephropathy, (iv) in Carpal tunnel deposits (beta2-microglobulin) of dialysis-related amyloidosis, (v) elastin fibers of skin dermis in actinic elastosis. These results indicate that X1, one of the main AGE-structures in vivo, plays an important role in aging and/or age-enhanced disease processes such as diabetic complications and atherosclerosis of vascular walls.