Regulation of 25-hydroxyvitamin D-3 1 alpha-hydroxylase gene expression byparathyroid hormone and 1,25-dihydroxyvitamin D-3

The conversion of 25-hydroxyvitamin D-3 to 1,25-dihydroxyvitamin D-3 (1,25- (OH)(2)D-3) takes place mainly in the kidney and is catalyzed by the enzyme 1 alpha-hydroxylase, Parathyroid hormone (PTH) and 1,25-(OH)(2)D-3 are wel l-known regulators of this tightly controlled step, but the mechanisms by w hich they modulate 1 alpha-hydroxylase activity have not been fully delinea ted. Northern analysis showed PTH and forskolin rapidly and transiently inc rease 1 alpha-hydroxylase expression in AOK-B50 cells and HKC-8 cells. Acti nomycin D treatment blocks the increase, but cycloheximide does not. No dec rease of 1 alpha-hydroxylase transcript by 1,25-(OH)(2)D-3 was observed in either cell line, although 24-hydroxylase levels were strongly induced by 1 ,25-(OH)(2)D-3 treatment. 1,25-(OH)(2)D-3 suppressed the 1 alpha-hydroxylas e transcript in vivo both in the presence and absence of exogenously suppli ed PTH, These results suggest that the stimulatory action of PTH is directl y on the 1 alpha-hydroxylase gene, while the repressive action of 1,25-(OH) (2)D-3 does not involve the parathyroid gland but is nevertheless indirect. (C) 2000 Academic Press.