Age- and gender-related differences in carbohydrate concentrations of a1-acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities

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• 作者：Satoshi Kishino ; Akikazu Nomura ; Shin Itoh ; Tsutomu Nakagawa ; Yoh Takekuma ; Mitsuru Sugawara ; Hiroyuki Furukawa ; Satoru Todo and Katsumi Miyazaki
• 刊名：European Journal of Clinical Pharmacology
• 出版年：2002
• 出版时间：December 2002
• 年：2002
• 卷：58
• 期：9
• 页码：621-628
• 全文大小：380 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1041

文摘

Objective. ŋ-acid glycoprotein (AAG) is a major binding protein for neutral and basic drugs because of its great drug affinity. AAG has three main genetic variants - F1, S, and A variants. Several attempts have been made to elucidate the differences in compositions of the carbohydrate moiety and structure-function relationships such as drug-binding differences. However, there have been few reports on age- and gender-related differences in compositions or concentrations of the carbohydrate moiety of AAG variants. The aim of this study was to clarify the age- and gender-related differences in carbohydrate concentrations and in drug-binding capacities of AAG glycoforms. Methods. The sera used in this study were obtained from 32 healthy subjects (17 men and 15 women, aged 16-84 years). The AAG glycoforms were isolated by hydroxyapatite chromatography. The binding capacity of AAG to disopyramide (DP), which is a basic drug, was determined using the ultrafiltration method. The concentrations of N-acetylneuraminic acid (NeuAc) and monosaccharides in AAG were determined using high-pH anion-exchange chromatography with pulsed-amperometric detection. Results. The mean plasma AAG concentration in the female subjects was significantly lower than that in the male subjects (0.67ǂ.12 mg/ml, mean-SD, in females, n=15, versus 0.81ǂ.17 mg/ml in males, n=17, P<0.05), but no age-related differences were found (0.75ǂ.18 mg/ml in young subjects, n=24, versus 0.77ǂ.12 mg/ml in older subjects, n=8, n.s.). However, the degree of branching of the glycan chain in the female subjects was significantly lower than that in the male subjects (1.61ǂ.17 mol/mol, mean-SD, in females, n=15, versus 1.75ǂ.23 mol/mol in males, n=17, P<0.05). There was a significant inverse relationship between the binding capacity of AAG to DP (Cb/AAG) and the degree of branching of the glycan chain. The binding capacity (Cb/AAG) decreased as the degree of branching in AAG glycans increased. The binding capacity (Cb/AAG) in the female subjects was significantly higher than that in the male subjects (2.79ǂ.59 mg/g AAG in females, mean-SD, n=15, versus 2.37ǂ.29 mg/g AAG in males, n=17, P<0.05). Conclusion. The degree of branching of the glycan chain in AAG plays an important role in drug-binding capacity. Gender-related differences in drug-binding capacity (Cb/AAG) may be caused by differences in the ratios of the extent of branching of the glycan chain in AAG.