EFFECT OF 3 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 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 (K(i)s 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.