Extrarenal Synthesis of 1,25-Dihydroxyvitamin D and Its Health Implications

Abstract

Although the kidney was initially thought to be the sole organ responsible for the production of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] via its enzyme CYP27B1, it is now appreciated that the expression of CYP27B1 in tissues other than the kidney is widespread. However, the kidney is the major source for circulating 1,25(OH)2D. Therefore the existence of the capacity for extrarenal 1,25(OH)2D production begs the question why, and in particular whether the extrarenal production of 1,25(OH)2D has physiologic importance. In this chapter this question will be discussed. First a compilation of the extrarenal sites for CYP27B1 expression is provided. This is followed by a discussion of the regulation of CYP27B1 expression and activity in extrarenal tissues, pointing out that such regulation is tissue specific and different from that of CYP27B1 in the kidney. Finally the physiologic significance of extrarenal 1,25(OH)2D production is examined, with special focus on the role of CYP27B1 in regulation of cellular proliferation and differentiation, hormone secretion, and immune function. At this point the data do not clearly demonstrate an essential role for CYP27B1 expression in any tissue outside the kidney, but several examples pointing in this direction are provided. With the availability of the mouse enabling tissue-specific deletion of CYP27B1, the role of extrarenal CYP27B1 expression can now be addressed definitively.