24-Hydroxylation of 1,25-dihydroxyergocalciferol. An unambiguous deactivation process.
1,24,25-Trihydroxyergocalciferol was isolated from bovine kidney homogenates incubated with 1,25-dihydroxyergocalciferol and from chick kidney homogenates incubated with 24,25-dihydroxyergocalciferol. The identity was established by ultraviolet absorbance, sensitivity to periodate, nuclear magnetic resonance, and mass spectrometry. The new metabolite had an affinity equal to 1,24,25-trihydroxycholecalciferol for the bovine-thymus and chick-intestinal 1,25-dihydroxyvitamin D receptor and had an affinity twice that of 1,24,25-trihydroxycholecalciferol for the rat-intestinal receptor. It was 3- and 6-fold less competitive than either 1,25-dihydroxycholecalciferol or 1,24,25-trihydroxycholecalciferol, respectively, for the rat plasma vitamin D transport protein. 1,24,25-Trihydroxyergocalciferol was at least 10-fold less active than 1,25-dihydroxycholecalciferol, 1,25-dihydroxyergocalciferol, and 1,24,25-trihydroxycholecalciferol at stimulating intestinal-calcium transport and was also relatively ineffective at stimulating bone-calcium resorption in rats. Moreover, in rats, [3H]1,24,25-trihydroxyergocalciferol was cleared from plasma approximately 40% faster than [3H]1,24,25-trihydroxycholecalciferol. These data suggest that C-24 hydroxylation of 1,25-dihydroxyergocalciferol represents a significant in vivo deactivation step, whereas equivalent deactivation of 1,25-dihydroxycholecalciferol seems to involve metabolic steps subsequent to C-24 hydroxylation (C-24 ketonization). C-24 ketonization of 1,25-trihydroxyergocalciferol would not be anticipated due to the presence of the 24(S)-methyl group. These results reveal further dissimilarities between ergocalciferol and cholecalciferol metabolism in mammals and suggest a mechanism for the lesser tendency of ergocalciferol to cause hypercalcemia relative to cholecalciferol.
D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002645:Chickens; D004872:Ergocalciferols / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006900:Hydroxylation; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051381:Rats; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000378:metabolism
D004872:Ergocalciferols; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D014809:Vitamin D-Binding Protein; C048827:1,24,25-trihydroxyergocalciferol; C003564:1,25-dihydroxyergocalciferol; C028140:24,25-dihydroxyvitamin D2; D002118:Calcium