McCarter J D, Adam M J, Hartman N G, Withers S G
Department of Chemistry, University of British Columbia, Vancouver, Canada.
Biochem J. 1994 Jul 15;301 ( Pt 2)(Pt 2):343-8. doi: 10.1042/bj3010343.
2-Deoxy-2-fluoro-beta-glucosyl and -beta-mannosyl fluorides administered to rats in a single dose (10 mg/kg) inhibited beta-glucosidase and beta-mannosidase activity respectively after 1 h in brain, spleen, liver and kidney tissues. This inhibition, presumably caused by accumulation of 2-deoxy-2-fluoroglycosyl-enzyme intermediates, indicates that intact 2-deoxy-2-fluoroglycosyl fluorides are distributed to these organs and, in the case of brain, that they cross the blood/brain barrier. beta-Glucosidase activity recovered completely or partially in brain, spleen, liver and kidney by 20-48 h. beta-Mannosidase activity partially recovered in all tissues by 48 h. beta-Galactosidase activity in brain and kidney was not significantly affected by administration of either the gluco or manno compounds at this dosage, indicating that these inhibitors are directed towards specific glycosidases. Observation of similar relatively rapid rates of beta-glycosidase re-activation in vivo and in tissue homogenates in vitro at 37 degrees C suggests that hydrolysis or transglycosylation of 2-deoxy-2-fluoroglycosyl-enzymes, not protein synthesis, are the primary mechanisms involved in the recovery of glycosidase activity inhibited by this class of compounds in vivo.
以单剂量（10毫克/千克）给大鼠注射2-脱氧-2-氟-β-葡萄糖苷氟化物和2-脱氧-2-氟-β-甘露糖苷氟化物后，1小时后在脑、脾、肝和肾组织中分别抑制了β-葡萄糖苷酶和β-甘露糖苷酶的活性。这种抑制作用可能是由2-脱氧-2-氟糖基-酶中间体的积累引起的，这表明完整的2-脱氧-2-氟糖基氟化物分布到了这些器官，就脑而言，它们穿过了血脑屏障。β-葡萄糖苷酶活性在20-48小时内在脑、脾、肝和肾中完全或部分恢复。β-甘露糖苷酶活性在48小时内在所有组织中部分恢复。在这个剂量下，给大鼠注射葡萄糖或甘露糖化合物对脑和肾中的β-半乳糖苷酶活性没有显著影响，这表明这些抑制剂针对的是特定的糖苷酶。在37摄氏度下，体内和体外组织匀浆中β-糖苷酶重新激活的相对快速速率相似，这表明2-脱氧-2-氟糖基-酶的水解或转糖基化作用而非蛋白质合成是这类化合物在体内抑制的糖苷酶活性恢复的主要机制。
