Constantopoulos G, Rees S, Cragg B G, Barranger J A, Brady R O
Proc Natl Acad Sci U S A. 1980 Jun;77(6):3700-4. doi: 10.1073/pnas.77.6.3700.
Intracerebral injection of the trypanocidal drug suramin in rats caused the formation of membranous neuronal and neuroglial inclusions. Here we show that intravenous administration suramin, 500 mg/kg, to 2-month-old rats causes a 5- to 8-fold increase of glycosaminoglycan concentration in the liver within 10 days and a 6-fold increase in urinary glycosaminoglycan excertion. The excess glycosaminoglycans consist of heparan sulfate and dermatan sulfate. Intracerebral injection of 250 micrograms of suramin results in a small increase of glycosaminoglycan and larger increase of ganglioside GM2, GM3, and GD3 concentrations in the treated region of the brain. The activities of the lysosomal enzymes iduronate sulfatase, beta-glucuronidase, and hyaluronidase in the liver of the suramin-treated mature rats were consistently decreased, whereas those of alpha-L-iduronidase, heparan N-sulfatase, arylsulfatase B, and others were considerably increased. The activity of iduronate sulfatase was completely inhibited in vitro by suramin at concentrations of 50 microM or higher. The activity of beta-glucuronidase was also strongly inhibited by low concentrations of suramin, but this inhibition was partially decreased at higher concentrations of the drug. The inhibition of both enzymes by suramin was noncompetitive. The suramin-treated rat may be a useful experimental animal model of mucopolysaccharidosis.
给大鼠脑内注射杀锥虫药苏拉明会导致膜性神经元和神经胶质包涵体的形成。在此我们表明，给2月龄大鼠静脉注射500mg/kg的苏拉明，在10天内会使肝脏中糖胺聚糖浓度增加5至8倍，尿中糖胺聚糖排泄量增加6倍。过量的糖胺聚糖由硫酸乙酰肝素和硫酸皮肤素组成。脑内注射250微克苏拉明会使脑内治疗区域的糖胺聚糖略有增加，神经节苷脂GM2、GM3和GD3浓度大幅增加。在接受苏拉明治疗的成年大鼠肝脏中，溶酶体酶艾杜糖醛酸硫酸酯酶、β-葡萄糖醛酸酶和透明质酸酶的活性持续降低，而α-L-艾杜糖醛酸酶、硫酸乙酰肝素N-硫酸酯酶、芳基硫酸酯酶B等的活性则显著增加。在体外，50微摩尔或更高浓度的苏拉明可完全抑制艾杜糖醛酸硫酸酯酶的活性。低浓度的苏拉明也能强烈抑制β-葡萄糖醛酸酶的活性，但在较高药物浓度下这种抑制作用会部分减弱。苏拉明对这两种酶的抑制作用是非竞争性的。经苏拉明处理的大鼠可能是一种有用的黏多糖贮积症实验动物模型。
