Long-term administration of vitamin D3 metabolites alters PTH-responsive osteoblastic adenylate cyclase in rats

We have examined the effect of induced hyper D3 vitaminosis on bone-related variables in the rat with special reference to the parathyroid (PTH)-sensitive adenylate cyclase (AC) in rat calvariae. Subcutaneous injections three times a week of doses theoretically corresponding to about 10 times the average physiological serum levels of either 25 hydroxyvitamin D3 (25OHD3), 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), or 24,25 dihydroxyvitamin D3 (24,25(OH)2D3) for 12 weeks gave the following results: At 12 weeks of treatment, 24,25(OH)2D3 levels in the groups receiving 25OHD3 or 24,25(OH)2D3 increased significantly, whereas 1,25(OH)2D3 levels remained unaffected. Correspondingly, PTH-sensitive AC activities in crude calvarial membrane fractions from 25OHD3- and 24,25(OH)2D3-treated animals were obliterated. This effect was apparent after 4 weeks of treatment. In the group receiving 25OHD3, both basal, plus Gpp(NH)p-, and forskolin-sensitive AC activities were significantly reduced after 4 weeks of treatment. Similar effects in crude kidney membrane fractions were, however, not observed. Liver membranes from 25OHD3- or 24,25(OH)2D3-treated animals showed insignificant changes in the isoprenalin-, PGE1-, Gpp(NH)p-, or forskolin-sensitive AC activities. Finally, the significance of reduced PTH-sensitive bone AC activity has been assessed. 25OHD3 treatment yielded normocalcemic and hypercalciuric rats, whereas 1,25(OH)2D3 enhanced both serum and urine Ca2+ levels. 24,25(OH)2D3-treated and control animals were undiscernible in this respect. However, the 24,25-(OH)2D3 treatment caused reductions in both serum alkaline phosphatase levels and urinary hydroxyproline/creatinine ratio.(ABSTRACT TRUNCATED AT 250 WORDS)