RT Journal Article
SR Electronic
T1 Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D<sub>3</sub>-3-<em>O</em>-Sulfate, a Major Circulating Vitamin D Metabolite in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 367
OP 379
DO 10.1124/dmd.117.078428
VO 46
IS 4
A1 Timothy Wong
A1 Zhican Wang
A1 Brian D. Chapron
A1 Mizuki Suzuki
A1 Katrina G. Claw
A1 Chunying Gao
A1 Robert S. Foti
A1 Bhagwat Prasad
A1 Alenka Chapron
A1 Justina Calamia
A1 Amarjit Chaudhry
A1 Erin G. Schuetz
A1 Ronald L. Horst
A1 Qingcheng Mao
A1 Ian H. de Boer
A1 Timothy A. Thornton
A1 Kenneth E. Thummel
YR 2018
UL http://dmd.aspetjournals.org/content/46/4/367.abstract
AB Metabolism of 25-hydroxyvitamin D3 (25OHD3) plays a central role in regulating the biologic effects of vitamin D in the body. Although cytochrome P450–dependent hydroxylation of 25OHD3 has been extensively investigated, limited information is available on the conjugation of 25OHD3. In this study, we report that 25OHD3 is selectively conjugated to 25OHD3-3-O-sulfate by human sulfotransferase 2A1 (SULT2A1) and that the liver is a primary site of metabolite formation. At a low (50 nM) concentration of 25OHD3, 25OHD3-3-O-sulfate was the most abundant metabolite, with an intrinsic clearance approximately 8-fold higher than the next most efficient metabolic route. In addition, 25OHD3 sulfonation was not inducible by the potent human pregnane X receptor agonist, rifampicin. The 25OHD3 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 SULT2A1 (rs296361; minor allele frequency = 15% in whites) and liver cytosolic SULT2A1 content as well as 25OHD3-3-O-sulfate formation rate, suggesting that variation in the SULT2A1 gene contributes importantly to interindividual differences in vitamin D homeostasis. Finally, 25OHD3-3-O-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 25OHD3-3-O-sulfate appear to be protected from rapid renal elimination, raising the possibility that the sulfate metabolite may serve as a reservoir of 25OHD3 in vivo, and contribute indirectly to the biologic effects of vitamin D.