Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D-3--Sulfate, a Major Circulating Vitamin D Metabolite in Humans.

Metabolism of 25-hydroxyvitamin D (25OHD) plays a central role in regulating the biologic effects of vitamin D in the body. Although cytochrome P450-dependent hydroxylation of 25OHD has been extensively investigated, limited information is available on the conjugation of 25OHD In this study, we report that 25OHD is selectively conjugated to 25OHD-3--sulfate by human sulfotransferase 2A1 (SULT2A1) and that the liver is a primary site of metabolite formation. At a low (50 nM) concentration of 25OHD, 25OHD-3--sulfate was the most abundant metabolite, with an intrinsic clearance approximately 8-fold higher than the next most efficient metabolic route. In addition, 25OHD sulfonation was not inducible by the potent human pregnane X receptor agonist, rifampicin. The 25OHD sulfonation rates in a bank of 258 different human liver cytosols were highly variable but correlated with the rates of dehydroepiandrosterone sulfonation. Further analysis revealed a significant association between a common single nucleotide variant within intron 1 of (rs296361; minor allele frequency = 15% in whites) and liver cytosolic SULT2A1 content as well as 25OHD-3--sulfate formation rate, suggesting that variation in the gene contributes importantly to interindividual differences in vitamin D homeostasis. Finally, 25OHD-3--sulfate exhibited high affinity for the vitamin D binding protein and was detectable in human plasma and bile but not in urine samples. Thus, circulating concentrations of 25OHD-3--sulfate appear to be protected from rapid renal elimination, raising the possibility that the sulfate metabolite may serve as a reservoir of 25OHD in vivo, and contribute indirectly to the biologic effects of vitamin D.