clude the liver and intestinal CYPs that are known to metabolize vitamin D compounds differently, such as CYP27A1, which 25-hydroxylates vitamin D3 and 24-hydroxylates vitamin D2 (Guo et al., 1993), and CYP3A4, which 24- and 25-hydroxylates vitamin D2 substrates more efficiently than vitamin D3 substrates (Gupta et al., 2004, 2005) and 23R- and 24S-hydroxylates 1α,25(OH)2D3 (Xu et al., 2006); the latter enzyme has recently been shown to be selectively induced by 1α,25(OH)2D in the intestine (Thompson et al., 2002; Xu et al., 2006). Both CYP27A1 and CYP3A4 are known to have significantly lower Michaelis-Menten constants (Km values) for 25OHD3 compared with CYP2R1 (Guo et al., 1993; Sawada et al., 2000), in the micromole per liter range; this questions their physiological but not their pharmacological relevance. Recent work (Helvig et al., 2008; Jones et al., 2009) has shown that both human intestinal microsomes and recombinant CYP3A4 protein break down 1α,25(OH)2D2 at a significantly faster rate than 1α,25(OH)2D3, suggesting that this non-specific CYP might limit vitamin D2 action preferentially in target cells, where it is expressed and when the substrate is in the pharmacological dose range. The same type of mechanism involving differential induction of non-specific CYPs may underlie the occasional reports of co-administered drug classes, such as anticonvulsants (Christiansen et al., 1975; Tjellesen et al., 1985; Hosseinpour et al., 2007), causing accelerated degradation of one vitamin D form over the other.
Adipose tissue stores of vitamin D probably represent “non-specific” stores sequestered because of the hydrophobic nature of vitamin D, but the extent to which the processes of accumulation or mobilization are regulated by normal physiological mechanisms remains unknown at this time. Rosenstreich et al. (1971) first identified adipose tissue as the primary site of vitamin D accumulation from experiments in which radiolabeled vitamin D was administered to vitamin D–deficient rats. Tissue levels of radioactivity measured during vitamin D repletion and during a subsequent period of deprivation showed that adipose tissue acquired the greatest quantity of radioactive compound and had the slowest rate of release. Work by Liel et al. (1988) suggested that there was enhanced uptake and clearance of vitamin D by adipose tissue in obese subjects compared with those of normal weights. Similarly, Wortsman et al. (2000) concluded that in obese subjects, vitamin D was stored in adipose tissue and not released when needed. Finally, Blum et al. (2008) found that, in elderly subjects supplemented with 700 IU of vitamin D per day, for every additional 15 kg of weight above “normal” at baseline, the mean adjusted change in 25OHD level was approximately 10 nmol/L lower after 1 year of supplementation.