@article {Gaodmd.117.078881, author = {Chunying Gao and Michael Z. Liao and Lyrialle W. Han and Kenneth E. Thummel and Qingcheng Mao}, title = {Hepatic transport of 25-hydroxyvitamin D3 conjugates: a mechanism of 25-hydroxyvitamin D3 delivery to the intestinal tract}, elocation-id = {dmd.117.078881}, year = {2018}, doi = {10.1124/dmd.117.078881}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 sulfonation 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, bioactivated, and exert 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, MRP3, MRP4, 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 vitamin D3, providing an alternative pathway of vitamin D delivery to the intestinal tract, which can be critical for vitamin D receptor-dependent gene regulation in enterocytes.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2018/02/21/dmd.117.078881}, eprint = {https://dmd.aspetjournals.org/content/early/2018/02/21/dmd.117.078881.full.pdf}, journal = {Drug Metabolism and Disposition} }