Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation
Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation
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DOI：
10.1172/jci9711
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发表时间：
2000-06-01
影响因子：
15.9
通讯作者：
Shayman, JA
中科院分区：
文献类型：
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作者：
Abe, A;Gregory, S;Shayman, JA
我们使用一种有效的葡萄糖神经酰胺合酶抑制剂来测试底物剥夺是否可以降低α-半乳糖苷酶A（α-galA）基因敲除小鼠（法布里病模型）中的神经酰胺三己糖苷水平。用D-苏型-1-亚乙二氧基苯基-2-棕榈酰氨基-3-吡咯烷基-丙醇（D-t-EtDO-P4）每日两次给药3天的C57 BL/6小鼠显示肾脏、肝脏和脾脏中葡糖神经酰胺水平呈浓度依赖性降低。单次腹膜内注射D-t-EtDO-P4导致肾脏葡萄糖神经酰胺减少55%，与快速肾脏葡萄糖神经酰胺代谢一致。在用D-t-EtDO-P4处理4周的α-GalA（-）雄性动物中观察到肾脏和肝脏神经酰胺三己糖苷水平的浓度依赖性降低。当S周龄α-Gal A（-）雄性动物接受10 mg/kg每日两次给药8周时，肾脏神经酰胺三己糖苷下降至起始水平以下，与神经酰胺三己糖苷降解的α-半乳糖苷酶A非依赖性补救途径一致。使用另一种葡糖神经酰胺合酶抑制剂N-丁基脱氧野尻霉素观察到的并发症，包括体重减轻和淋巴器官的无细胞性，在使用D-t-EtDO-P4时未观察到。这些数据表明，法布里病可能适合底物剥夺疗法。
We used a potent inhibitor of glucosylceramide synthase to test whether substrate deprivation could lower globotriaosylceramide levels in alpha-galactosidase A (alpha-galA) knockout mice, a model of Fabry disease. C57BL/6 mice treated twice daily for 3 days with D-threo- 1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (D-t-EtDO-P4) showed a concentration-dependent decrement in glucpsylceramide levels in kidney, liver, and spleen. A single intraperitoneal injection of D-t-EtDO-P4 resulted in a 55% reduction in renal glucosylceramide, consistent with rapid renal glucosylceramide metabolism. A concentration-dependent decrement in renal and hepatic globotriaosylceramide levels was observed in alpha-GalA(-) males treated for 4 weeks with D-t-EtDO-P4. When S-week-old alpha-Gal A(-) males were treated for 8 weeks with 10 mg/kg twice daily, renal globotriaosylceramide fell to below starting levels, consistent with an a-galactosidase A-independent salvage pathway for globotriaosylceramide degradation. Complications observed with another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, including weight loss and acellularity of lymphatic organs, were not observed with D-t-EtDO-P4. These data suggest that Fabry disease may be amenable to substrate deprivation therapy.