Extra Renal 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(OH) 2 D 3 via its enzyme CYP27b1, it is now appreciated that the expression of CYP27b1 in tissues other than the kidney is wide spread. However, the kidney is the major source for circulating 1,25(OH) 2 D 3 . Therefore the existence of the capacity for extra renal 1,25(OH) 2 D 3 production begs the question why, and in particular whether the extra renal production of 1,25(OH) 2 D 3 has physiologic importance. In this chapter this question will be discussed. First a compilation of the extra renal sites for CYP27b1 expression is provided. This is followed by a discussion of the regulation of CYP27b1 expression and activity in extra renal tissues, pointing out that such regulation is tissue specific and different from that of CYP27b1 in the kidney. Finally the physiologic significance of extra renal 1,25(OH) 2 D 3 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 extra renal CYP27b1 expression can now be addressed definitively.

Current Controversies

“…As we will discuss subsequently, most tissues expressing CYP27B1 rely on the free 25OHD level in blood for their available substrate, whereas the kidney tubule has a mechanism for taking up 25OHD still bound to its major binding protein, vitamin D binding protein (DBP). Moreover, regulation of the extrarenal CYP27B1 differs from that of the renal CYP27B1 (review in [10]). The renal 1α-hydroxylase is tightly regulated primarily by three hormones: parathyroid hormone (PTH) (stimulatory), FGF23 (inhibitory), and 1,25(OH 2 D itself (inhibitory).…”

Vitamin D cell signalling in health and disease

“…Vitamin D has an important role in the innate immune response and its deficiency is linked to a number of infectious diseases such as tuberculosis, septicaemia, influenza, pneumonia and periodontal disease [3,334,335]. Adequate levels of vitamin D are required to initiate antimicrobial responses [336,337].…”

Vitamin D: newly discovered actions require reconsideration of physiologic requirements

“…Thus it has been suspected for some time that vitamin D exerts its actions not only on classic tissues regulating calcium homeostasis such as bone, gut and kidney, but also on other tissues. Indeed, many of these tissues also contain the enzyme, CYP27B1 [1], which converts the major circulating metabolite of vitamin D, 25 hydroxyvitamin D (25OHD), to 1,25(OH) 2 D. This enzyme, originally thought to be found only in the kidney, is now known to contribute to local production of 1,25(OH) 2 D 3 [1] and to tissue-specific responses to vitamin D. Furthermore, regulation of CYP27B1 in non-renal tissues generally differs from that in the kidney, and may be more dependent on the concentration of available 25OHD substrate [1]. This has led to the concept that maintenance of 25OHD levels in the blood above that required for the prevention of rickets and osteomalacia is required for vitamin D regulation of a large number of physiologic functions beyond that of its classic actions in bone mineral metabolism.…”