Grün B R, Berger U, Oberdorfer F, Hull W E, Ostertag H, Keppler D
Deutsches Krebsforschungszentrum, Heidelberg, F.R.G.
Adv Enzyme Regul. 1990;30:231-42. doi: 10.1016/0065-2571(90)90020-3.
The metabolism of 2-deoxy-2-fluoro-D-galactose (dGalF) was studied in rodents using HPLC, enzymatic methods, and 19F-NMR spectroscopy in vivo and in vitro. The liver took up the major part of the administered dose of the 14C-labeled D-galactose analog. This was confirmed in vivo by use of the 18F-labeled sugar (1.5 mCi/kg; 25 mumol/kg) and examination by positron emission tomography. After a dose of 1 mmol/kg, dGalF-1-phosphate accumulated rapidly (5.3 +/- 0.4 mmol/kg after 30 min), followed by formation of UDP-dGalF and UDP-2-deoxy-2-fluoro-D-glucose (0.7 +/- 0.1 and 1.8 +/- 0.1 mmol/kg, respectively, after 5 hr). Good quantitative agreement was obtained between the measurements by HPLC and enzymatic analyses and by 19F-NMR. The noninvasive in vivo 19F-NMR technique is particularly advantageous, since it allows the simultaneous analysis of all dGalF metabolites. The diversion of uridylate, due to the accumulation of UDP-2-deoxy-2-fluoro-D-hexoses, was associated with a rapid depletion of hepatic UTP, UDP-glucose, and UDP-galactose. The UTP content was decreased to 11 +/- 6% of normal within 15 min after administration of dGalF at a dose of 1 mmol/kg. The UTP-depleting action was minimal, however, at a dose of 25 mumol/kg or less, indicating that interference in uridylate metabolism will be negligible at the doses required for positron emission tomography of the liver using the 18F-labeled compound. At higher doses the UTP deficiency induced by dGalF may be useful in the chemotherapy of D-galactose-metabolizing tumors such as hepatocellular carcinoma. At moderate doses of dGalF, 19F-NMR spectroscopy in vivo or in vitro could be used to pinpoint defects of the enzymes that cause galactosemia, i.e. of galactokinase, uridyltransferase, or 4-epimerase.
利用高效液相色谱法（HPLC）、酶法以及体内外19F-核磁共振波谱法，在啮齿动物中研究了2-脱氧-2-氟-D-半乳糖（dGalF）的代谢情况。肝脏摄取了所给予的14C标记的D-半乳糖类似物剂量的主要部分。通过使用18F标记的糖（1.5毫居里/千克；25微摩尔/千克）并采用正电子发射断层扫描进行检查，在体内证实了这一点。给予1毫摩尔/千克的剂量后，dGalF-1-磷酸迅速积累（30分钟后为5.3±0.4毫摩尔/千克），随后形成UDP-dGalF和UDP-2-脱氧-2-氟-D-葡萄糖（5小时后分别为0.7±0.1和1.8±0.1毫摩尔/千克）。HPLC、酶分析以及19F-核磁共振测量结果之间在定量上具有良好的一致性。非侵入性的体内19F-核磁共振技术特别有利，因为它能够同时分析所有dGalF代谢物。由于UDP-2-脱氧-2-氟-D-己糖的积累导致尿苷酸转移，这与肝脏中UTP、UDP-葡萄糖和UDP-半乳糖的快速消耗有关。给予1毫摩尔/千克的dGalF后15分钟内，UTP含量降至正常水平的11±6%。然而，在25微摩尔/千克或更低的剂量下，UTP消耗作用最小，这表明在使用18F标记化合物对肝脏进行正电子发射断层扫描所需的剂量下，对尿苷酸代谢的干扰可以忽略不计。在较高剂量下，dGalF诱导的UTP缺乏可能在治疗诸如肝细胞癌等D-半乳糖代谢性肿瘤的化疗中有用。在中等剂量的dGalF下，体内或体外的19F-核磁共振波谱法可用于确定导致半乳糖血症的酶，即半乳糖激酶、尿苷酸转移酶或4-表异构酶的缺陷。
