Metabolism and binding properties of 24,24-difluoro-25-hydroxyvitamin D3.
To evaluate possible functional roles for 24,25-dihydroxyvitamin D3, 24,24-difluoro-25-hydroxyvitamin D3 has been synthesized and shown to be equally as active as 25-hydroxyvitamin D3 in all known functions of vitamin D. The use of the difluoro compound for this purpose is based on the assumption that the C-F bonds are stable in vivo and that the fluorine atom does not act as hydroxyl in biological systems. No 24,25-dihydroxyvitamin D3 was detected in the serum obtained from vitamin D-deficient rats that had been given 24,24-difluoro-25-hydroxyvitamin D3, while large amounts were found when 25-hydroxyvitamin D3 was given. Incubation of the 24,24-difluoro compound with kidney homogenate prepared from vitamin D-replete chickens failed to produce 24,25-dihydroxyvitamin D3, while the same preparations produced large amounts of 24,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Kidney homogenate prepared from vitamin D-deficient chickens produced 24,24-difluoro-1,25-dihydroxyvitamin D3 from 24,24-difluoro-25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. In binding to the plasma transport protein for vitamin D compounds, 24,24-difluoro-25-hydroxyvitamin D3 is less active than 25-hydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3. In binding to the chick intestinal cytosol receptor, 24,24-difluoro-25-hydroxyvitamin D3 is more active than 25-hydroxyvitamin D3 which is itself more active than 24R,25-dihydroxyvitamin D3. The 24,24-difluoro-1,25-dihydroxyvitamin D3 is equal to 1,25-dihydroxyvitamin D3, and both are 10 times more active than 1,24R,25-trihydroxyvitamin D3 in this system. These results provide strong evidence that the C-24 carbon of 24,24-difluoro-25-hydroxyvitamin D3 cannot be hydroxylated in vivo, and, further, the 24-F substitution acts similar to H and not to OH in discriminating binding systems for vitamin D compounds.
D000818:Animals; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002117:Calcitriol / Q000378:metabolism*; D002645:Chickens; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051381:Rats
D001798:Blood Proteins; C020614:24,24-difluoro-25-hydroxyvitamin D3; D002117:Calcitriol; D002112:Calcifediol