|Reinhardt, Timothy - Tim|
Submitted to: Biochemical Pharmacology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/10/2000
Publication Date: N/A
Citation: Interpretive Summary: Vitamin D is required for the body to build strong, healthy bones and teeth. In order to do its job, vitamin D must be "activated". The activated form of vitamin D, which is also known as 1,25-dihydroxyvitamin D, then acts at the intestine and kidney to cause calcium to enter the body and blood calcium to be elevated. Sometimes this system breaks down and results in metabolic diseases such as milk fever in dairy cattle and osteoporosis in humans. During investigations determining how vitamin D is activated, as well as deactivated, we discovered another active form of vitamin D, namely 1,24-dihydroxyvitamin D2. In the present work we found that this compound can also stimulate the intestine, kidney and other tissues, but unlike 1,25-dihydroxyvitamin D, it did not result in potentially harmful elevation in blood calcium. This combination of characteristics suggests that 1,24-dihydroxyvitamin D2 could be a safe therapeutic agent and could be of benefit in developing various strategies for treating milk fever and other metabolic disorders in human and veterinary medicine.
Technical Abstract: Experiments were conducted to compare the relative hypercalcuric and hypercalcemic activities of 1,24-(OH)2D2, 1,24-(OH)2D3, and 1,25-(OH)2D3 in 7-wk-old rats. Rats were dosed orally with each sterol for 7 d at a rate of 1 ng/g BW/d. We also monitored the effect of the 3 compounds on the induction of mRNA for CaATPase and for 25-hydroxyvitamin D-24-hydroxyla a the kidney and intestine, on plasma vitamin D metabolite levels, and on the capacity to evoke modification in the VDR/RXR heterodimer conformation. Plasma Ca was elevated in the rats treated with 1,24-(OH)2D3 and 1,25-(OH)2D3, but not in the 1,24-(OH)2D2-dosed rats. Urinary Ca was significantly elevated in all groups. Duodenal PMCA mRNA was elevated to a similar extent in all groups relative to controls. Duodenal 24-hydroxylase mRNA was elevated in all groups relative to controls. Kidney 24-hydroxylase was also significantly elevated in the 1,24-(OH)2D3- and 1,25-(OH)2D3-treated rats but not in the 1,24-(OH)2D2-tr rats. Recombinant hVDR extracts were incubated with saturating concentrations of 1,24-(OH)2D2, 1,24-(OH)2D3 and 1,25-(OH)2D3 and analyzed by EMSA. Overall binding was comparable for all metabolites; however the 1,24-(OH)2D2 and complex exhibited distinctly altered mobility relative to 1,24-(OH)2D3 and 1,25-(OH)2D3 suggestive of an effect on hVDR/hRXR conformation. These data suggest that 1,24-(OH)2D2 is not as potent as either of the vitamin D3 sterols at affecting hypercalcemia or hypercalcuria in young growing rats; however, 1,24-(OH)2D2 can evoke other biological responses similar to the vitamin D3 sterols. These different responses may be related to the alterations in conformation state of the hVDR/hRXR heterodimer.