%0 Journal Article %A Chunying Gao %A Michael Z. Liao %A Lyrialle W. Han %A Kenneth E. Thummel %A Qingcheng Mao %T Hepatic transport of 25-hydroxyvitamin D3 conjugates: a mechanism of 25-hydroxyvitamin D3 delivery to the intestinal tract %D 2018 %R 10.1124/dmd.117.078881 %J Drug Metabolism and Disposition %P dmd.117.078881 %X Vitamin D3 is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25OHD3, the most abundant circulating metabolite of vitamin D3, is further transformed to the biologically active metabolite 1α,25-(OH)2D3 by CYP27B1 in the kidney and extra-renal tissues, and to non-active metabolites by other CYP enzymes. In addition, 25OHD3 undergoes sulfation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD3-3-O-sulfate (25OHD3-S) and 25OHD3-3-O-glucuronide (25OHD3-G), both of which were detected in human blood and bile. Considering that the conjugates excreted into the bile may be circulated to and reabsorbed from the intestinal lumen, deconjugated to 25OHD3 and then converted to 1α,25-(OH)2D3, exerting local intestinal cellular effects, it is crucial to characterize enterohepatic transport mechanisms of 25OHD3-S and 25OHD3-G, and thereby understand and predict mechanisms of inter-individual variability in mineral homeostasis. In the present study, with plasma membrane vesicle and cell-based transport studies, we showed that 25OHD3-G is a substrate of MRP2, MRP3, OATP1B1 and OATP1B3, and that 25OHD3-S is likely a substrate of BCRP, OATP2B1 and OATP1B3. We also demonstrated sinusoidal and canalicular efflux of both conjugates using sandwich cultured human hepatocytes. Given substantial expression of these transporters in liver hepatocytes and intestinal enterocytes, this study demonstrates for the first time that transporters could play important roles in the enterohepatic circulation of 25OHD3 conjugates, providing an alternative pathway of 25OHD3 delivery to the intestinal tract, which could be critical for vitamin D receptor-dependent gene regulation in enterocytes. %U https://dmd.aspetjournals.org/content/dmd/early/2018/02/26/dmd.117.078881.full.pdf