1. Metabolism and Catabolism of Vitamin D, Its Metabolites and Clinically Relevant Analogs.
- Author
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Jones, Glenville
- Abstract
This chapter discusses the current state of knowledge of vitamin D metabolism and the specific enzymes involved. Vitamin D
3 undergoes a two-step metabolic activation involving sequential hydroxylations at 25- and 1α-carbons by cytochrome P450-based hydroxylases (CYP2R1 and CYP27B1) to give first the main circulating form 25-hydroxyvitamin D3 and then a hormonally active form 1α,25-dihydroxyvitamin D3 . The plant-derived vitamin D2 undergoes the same activation steps. This review highlights the recent finding of extra-renal sites of CYP27B1 expression and the physiological implications of this discovery. 1α,25-Dihydroxyvitamin D3 is inactivated by another cytochrome P450 enzyme (CYP24A1) which produces a series of metabolic products culminating in either a side chain-truncated biliary excretory form, calcitroic acid, or a 26,23-lactone derivative. This chapter also discusses the current knowledge of the metabolism of the clinically relevant analogs of vitamin D, ranging from prodrug forms (e.g. 1(OH)D) that require a step or more of activation to produce a biologically active form to the calcitriol analogs, which are active as administered. Differences between metabolism-sensitive and metabolism-resistant vitamin D analogs are discussed in the context of evaluating the relative importance of analog metabolism in their mechanism of action. The review ends by attempting to predict future directions in the field, focussing on determination of CYP structure, the knowledge gained from mouse CYP knockouts and future vitamin D drug design. [ABSTRACT FROM AUTHOR]- Published
- 2010
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