Opposing effects of cyclic adenosine-3',5'-monophosphate and cyclic guanosine-3',5'-monophosphate on the metabolism of 24-hydroxyvitamin D3 in isolated chick renal tubules.

Abstract

The conversion of 25-hydroxyvitamin D3 (25 OH D3) to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3) and 1,24,25-trihydroxyvitamin D3 (1.24,25-(OH)3D3) was studied in renal tubules prepared from chicks raised on a vitamin D deficient diet with or without vitamin D supplementation. As described previously, in tubules from vitamin D deficient chicks, cyclic AMP caused an increase in the net accumulation of 1,25-(OH)2D3, the major metabolite formed under these circumstances. This stimulation was shown to be due to an increased maximum velocity of the hydroxylation reaction. There was also a significant inhibition of the net accumulation of 24,25-(OH)2D3. Cyclic GMP caused a significant inhibition of 1,25-(OH)2D3 formation and stimulation of the net accumulation of 24,25-(OH)2D3. In chicks supplemented with high doses of vitamin D, 24,25-(OH)2D3 was the major metabolite of 25 OH D3 detected and 1-hydroxylase activity was negligible. Under these circumstances, neither cyclic AMP nor cyclic GMP affected net accumulation of 24,25(OH)2D3. This suggested that the apparent effect of the nucleotides on formation of 24,25-(OH)2D3 may have been due to further metabolism of 24,25-(OH)2D3 when 1-hydroxylase activity was high. It is concluded that cyclic AMp and cyclic GMP have reciprocal effects on renal 25 OH D3-1-hydroxylase activity, and both should be considered potential intracellular regulators of 25 OH D3 metabolism.