Extrarenal vitamin D hydroxylase expression and activity in normal and malignant cells: modification of expression by epigenetic mechanisms and dietary substances.

Epidemiological studies have demonstrated an inverse correlation between risk of several cancers, sun exposure, and serum levels of 25-hydroxyvitamin D3 (25-OH-D3). 1,2 While 25-OH-D3 is present in human serum at nanomolar concentrations, levels of the active vitamin D metabolite 1,25(OH)2D3 are in the picomolar range, i.e. a thousand-fold lower. These low 1,25(OH)2D3 levels are strictly regulated to maintain calcium and phosphate homeostasis. Renal 1,25(OH)2D3 synthesis is primarily stimulated by low serum calcium, and consequently by parathyroid hormone (PTH), which up-regulates 25-hydroxyvitamin D3 1 -hydroxylase expression (CYP27B1). In contrast, 1,25(OH)2D3 itself down-regulates CYP27B1 by negative feedback. Expression of the metabolizing hydroxylase CYP24A1 is under direct regulation of 1,25(OH)2D3, which, by binding to its vitamin D receptor (VDR), induces CYP24A1 levels rapidly and strongly. In addition to maintaining mineral ion homeostasis, 1,25(OH)2D3 is a potent inhibitor of proliferation and promotes differentiation and apoptosis in a variety of cancer cells in vitro, including cells derived from the colon. However, this occurs only at nanomolar concentrations, and it therefore seems unlikely that the picomolar levels present in serum could potentially protect against malignancies. Indeed, epidemiological studies demonstrated that normal to high levels of 1,25(OH)2D3 did not correlate inversely with tumor incidence. We demonstrated in human colonic cell lines, and other groups in cell lines derived from other organs, that non-renal cells can synthesize and degrade 1,25(OH)2D3 6