Opposing Effects of Cyclic Adenosine-3′,5′-Monophosphate and Cyclic Guanosine-3′,5′-Monophosphate on the Metabolism of 25-Hydroxyvitamin D₃ in Isolated Chick Renal Tubules

 

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Summary

The conversion of 25-hydroxyvitamin D₃ (25 OH D₃) to 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂ D₃), 24,25-dihydroxyvitamin D₃ (24,25-(OH)₂ D₃) and 1,24,25-trihydroxyvitamin D₃ (1,24,25-(OH)₃ D₃) 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)₂ D₃, 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)₂ D₃. Cyclic GMP caused a significant inhibition of 1,25-(OH)₂ D₃ formation and stimulation of the net accumulation of 24,25-(OH)₂ D₃. In chicks supplemented with high doses of vitamin D, 24,25-(OH)₂ D₃ 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)₂ D₃. This suggested that the apparent effect of the nucleotides on formation of 24,25-(OH)₂ D₃ may have been due to further metabolism of 24,25-(OH)₂ D₃ 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.