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Nonclassic Actions of Vitamin D

Department of Medicine and Dermatology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California 94121

Address all correspondence and requests for reprints to: Daniel Bikle, M.D., Ph.D., Veterans Affairs Medical Center (111N), 4150 Clement Street, San Francisco, California 94121. E-mail: daniel.bikle{at}ucsf.edu.

Context: Vitamin D receptors are found in most tissues, not just those participating in the classic actions of vitamin D such as bone, gut, and kidney. These nonclassic tissues are therefore potential targets for the active metabolite of vitamin D, 1,25(OH)₂D. Furthermore, many of these tissues also contain the enzyme CYP27B1 capable of producing 1,25(OH)₂D from the circulating form of vitamin D. This review was intended to highlight the actions of 1,25(OH)₂D in several of these tissues but starts with a review of vitamin D production, metabolism, and molecular mechanism.

Evidence Acquisition: Medline was searched for articles describing actions of 1,25(OH)₂D on parathyroid hormone and insulin secretion, immune responses, keratinocytes, and cancer.

Evidence Synthesis: Vitamin D production in the skin provides an efficient source of vitamin D. Subsequent metabolism to 1,25(OH)₂D within nonrenal tissues differs from that in the kidney. Although vitamin D receptor mediates the actions of 1,25(OH)₂D, regulation of transcriptional activity is cell specific. 1,25(OH)₂D inhibits PTH secretion but promotes insulin secretion, inhibits adaptive immunity but promotes innate immunity, and inhibits cell proliferation but stimulates their differentiation.

Conclusions: The nonclassic actions of vitamin D are cell specific and provide a number of potential new clinical applications for 1,25(OH)₂D₃ and its analogs. However, the use of vitamin D metabolites and analogs for these applications remains limited by the classic actions of vitamin D leading to hypercalcemia and hypercalcuria.

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