Vitamin D3-stimula Ted Template Activity of Chromatin from Rat

-Administration of vitamin D to rats deficient in this vitamin markedly increases the template activity for DNA-dependent RNA synthesis by rat intestinal mucosal chromatin. The maximum stimulation of template activity occurs three hours after a dose of 2000 international units of vitamin D3 is given. These results support the concept that vitamin D functions by initiating the transcription of DNA into mRNA, which codes for functional protein(s) involved in calcium transport in the small intestine. Introduction.-It is generally accepted that vitamin D stimulates the absorption of calcium in the small intestine and plays an important role in the mobilization of mineral from formed bone. These two physiologic actions are thought to work in concert to maintain the [Ca++] [HP04=] product in the blood at supersaturation levels with respect to bone mineral.1 Lund and DeLuca2 first showed that a polar compound designated as peak IV which is a major biologically active metabolite of vitamin D appears in many tissues after 3H-vitamin D administration. Stohs and DeLuca3 found that four or eight hours after intravenous injection of 10 international units (LU) (0.25 ,ug) of 3H-vitamin D3, the major site of accumulation of radioactivity in rat and chick intestinal mucosa is the nuclear membrane, and that the predominant form of the vitamin in the target tissues (intestine and bone) is a polar metabolite. The peak IV metabolite of vitamin D3 was recently identified by Blunt et al.4 as 25-hydroxycholecalciferol (25-HCC); this is approximately 1.4 times as active as vitamin D3 in curing rickets in rats and is also more active than vitamin D in chicks as determined by the bone ash assay (Blunt et al.5). The need for conversion of vitamin D to the metabolically active form at least in part explains the lag in physiologic action after vitamin D administration. After a rat deficient in vitamin D is given 100 IU (2.5 jig) of vitamin D3 intravenously, serum calcium does not begin to rise significantly for 8 to 12 hours. However, four to eight hours after 2.5 gg of 25-HCC is given, serum calcium is elevated (Blunt et al.5). Recent experiments indicate that 25-hydroxycholecalciferol may be the sole active form of vitamin D3 in the target tissues. Trummel et al.6 have shown that 0.9 IU/ml of 25-HCC stimulates mobilization of calcium from isolated embryonic bone, whereas 380 IU/ml vitamin D3 does not. In addition, Olson and DeLuca7 have shown that there is a very rapid rise in calcium transport in a perfused rat intestine after treatment in vitro with 2.5 ,.g of 25-HCC, whereas 500 ;Ag vitamin D3 has no effect. In 1964, Eisenstein and Passavoy8 found that actinomycin D, an inhibitor of DNA-directed RNA synthesis, blocks the hypercalcemic response to large doses