Effect of three A-ring analogs of 1 alpha,25-dihydroxyvitamin D3 on 25-OH-D3-1 alpha-hydroxylase in isolated mitochondria and on 25-hydroxyvitamin D3 metabolism in cultured kidney cells.
Three A-ring analogs of 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3)--2-nor-1,3-seco-1,25(OH)2D3 (2-nor analog), 2-oxa-3-deoxy-25-OH-D3 (2-oxa analog), and A-homo-3-deoxy-3,3-dimethyl-2,4-dioxa-25-OH-D3 (A-homo analog)--were tested for their ability to inhibit 25-OH-D3-1 alpha-hydroxylase (1 alpha-hydroxylase) in isolated mitochondria and to alter 25-OH-D3 metabolism in cultured chick kidney cells. The 2-nor and 2-oxa analogs were relatively potent (Kis of 60 and 30 nM, respectively, compared with 170 nM for 1,25(OH)2D3), whereas the A-homo analog was completely ineffective in inhibiting 1 alpha-hydroxylase activity. In contrast, all three analogs were able to repress 1 alpha-hydroxylase and induce 24-hydroxylase activity in cultured chick kidney cells, suggesting that this process is not one of direct action in the mitochondria, but is more likely to be a receptor-mediated one.
Henry
H L
HL
Department of Biochemistry, University of California, Riverside 92521.
Fried
S
S
Shen
G Y
GY
Barrack
S A
SA
Okamura
W H
WH
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive; D002112:Calcifediol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D002645:Chickens; D007668:Kidney / Q000378:metabolism* / Q000648:ultrastructure; D008928:Mitochondria / Q000201:enzymology*
C069817:2-nor-1,3-seco-1,25-dihydroxyvitamin D3; C069818:2-oxa-3-deoxy-25-hydroxyvitamin D3; C069819:A-homo-3-deoxy-3,3-dimethyl-2,4-dioxa-25-hydroxyvitamin D3; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol