Grant: Operating Grant: Industry-partnered Collaborative Research - Other Partner

Differences between vitamins D2 and D3 have been noted at the level of potency and toxicity for over 3 decades but never satisfactorily elucidated. Vitamin D2 with its additional C22-23 double bond and C24 methyl group as compared with vitamin D3 still undergoes successive steps of 25- and 1á-hydroxylation to give a 1á,25-dihydroxyvitamin D active form and this 'hormonal' form interacts with the vitamin D receptor to produce biological effects via a transcriptional mechanism. However, there have been many reports over the years that vitamin D2 metabolites and analogs are less potent or toxic that their vitamin D3 counterparts. Recently, this has become a critical public health issue in the aftermath of a paper by Armas et al (AJClinNutr 2004) who claimed that vitamin D2 preparations (used widely in supplements, drug formulations and in food fortification) are less effective that their vitamin D3 equivalent and that 25-OH-D2 is more rapidly degraded than its 25-OH-D3 counterpart. Though, this putative lower potency might be considered a disadvantage, vitamin D2 metabolites (eg 1á,25-(OH)2D2) are also less toxic, which offers some advantages in the treatment of secondary hyperparathyroidism, where 1á,25-(OH)2D3 is frequently associated with more hypercalcemic episodes and a narrow therapeutic window. The objectives of this proposal are to use modern metabolic and genetic animal models to explore the mechanistic basis for the metabolic differences in vitamin D2 and vitamin D3 metabolism.