In vivo metabolism and UTP-depleting action of 2-deoxy-2-fluoro-D-galactose.
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.
Grün
B R
BR
Deutsches Krebsforschungszentrum, Heidelberg, F.R.G.
Berger
U
U
Oberdorfer
F
F
Hull
W E
WE
Ostertag
H
H
Keppler
D
D
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005461:Fluorine; D005462:Fluorine Radioisotopes; D005643:Fucose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005690:Galactose; D006859:Hydrogen; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D014055:Tomography, Emission-Computed; D014544:Uridine Triphosphate / Q000378:metabolism*; D001743:Urinary Bladder / Q000000981:diagnostic imaging / Q000378:metabolism*
D005462:Fluorine Radioisotopes; D005461:Fluorine; D005643:Fucose; D006859:Hydrogen; C049289:2-deoxy-2-fluorogalactose; D014544:Uridine Triphosphate; D005690:Galactose