Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction]
Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Published 2018
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Published 2018
| Publication Date: |
2018-04-11
|
|---|---|
| Publisher: |
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
|
| Print ISSN: |
0090-9556
|
| Electronic ISSN: |
1521-009X
|
| Topics: |
Chemistry and Pharmacology
Medicine
|
| Published by: |
| _version_ | 1836398887021051904 |
|---|---|
| autor | Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. |
| beschreibung | Vitamin D 3 is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25-Hydroxyvitamin D 3 (25OHD 3 ), the most abundant circulating metabolite of vitamin D 3 , is further transformed to the biologically active metabolite 1 α ,25-dihydroxyvitamin D 3 (1 α ,25-(OH) 2 D 3 ) by CYP27B1 in the kidney and extrarenal tissues, and to nonactive metabolites by other cytochrome P450 enzymes. In addition, 25OHD 3 undergoes sulfation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD 3 -3- O -sulfate (25OHD 3 -S) and 25OHD 3 -3- O -glucuronide (25OHD 3 -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 25OHD 3 , and then converted to 1 α ,25-(OH) 2 D 3 , exerting local intestinal cellular effects, it is crucial to characterize enterohepatic transport mechanisms of 25OHD 3 -S and 25OHD 3 -G, and thereby understand and predict mechanisms of interindividual variability in mineral homeostasis. In the present study, with plasma membrane vesicle and cell-based transport studies, we showed that 25OHD 3 -G is a substrate of multidrug resistance proteins 2 and 3, OATP1B1, and OATP1B3, and that 25OHD 3 -S is probably a substrate of breast cancer resistance protein, 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 25OHD 3 conjugates, providing an alternative pathway of 25OHD 3 delivery to the intestinal tract, which could be critical for vitamin D receptor-dependent gene regulation in enterocytes. |
| citation_standardnr | 6231109 |
| datenlieferant | ipn_articles |
| feed_id | 1915 |
| feed_publisher | The American Society for Pharmacology and Experimental Therapeutics (ASPET) |
| feed_publisher_url | http://www.aspet.org/ |
| insertion_date | 2018-04-11 |
| journaleissn | 1521-009X |
| journalissn | 0090-9556 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | The American Society for Pharmacology and Experimental Therapeutics (ASPET) |
| quelle | Drug Metabolism and Disposition |
| relation | http://dmd.aspetjournals.org/cgi/content/short/46/5/581?rss=1 |
| search_space | articles |
| shingle_author_1 | Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. |
| shingle_author_2 | Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. |
| shingle_author_3 | Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. |
| shingle_author_4 | Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. |
| shingle_catch_all_1 | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] Vitamin D 3 is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25-Hydroxyvitamin D 3 (25OHD 3 ), the most abundant circulating metabolite of vitamin D 3 , is further transformed to the biologically active metabolite 1 α ,25-dihydroxyvitamin D 3 (1 α ,25-(OH) 2 D 3 ) by CYP27B1 in the kidney and extrarenal tissues, and to nonactive metabolites by other cytochrome P450 enzymes. In addition, 25OHD 3 undergoes sulfation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD 3 -3- O -sulfate (25OHD 3 -S) and 25OHD 3 -3- O -glucuronide (25OHD 3 -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 25OHD 3 , and then converted to 1 α ,25-(OH) 2 D 3 , exerting local intestinal cellular effects, it is crucial to characterize enterohepatic transport mechanisms of 25OHD 3 -S and 25OHD 3 -G, and thereby understand and predict mechanisms of interindividual variability in mineral homeostasis. In the present study, with plasma membrane vesicle and cell-based transport studies, we showed that 25OHD 3 -G is a substrate of multidrug resistance proteins 2 and 3, OATP1B1, and OATP1B3, and that 25OHD 3 -S is probably a substrate of breast cancer resistance protein, 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 25OHD 3 conjugates, providing an alternative pathway of 25OHD 3 delivery to the intestinal tract, which could be critical for vitamin D receptor-dependent gene regulation in enterocytes. Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. The American Society for Pharmacology and Experimental Therapeutics (ASPET) 0090-9556 00909556 1521-009X 1521009X |
| shingle_catch_all_2 | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] Vitamin D 3 is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25-Hydroxyvitamin D 3 (25OHD 3 ), the most abundant circulating metabolite of vitamin D 3 , is further transformed to the biologically active metabolite 1 α ,25-dihydroxyvitamin D 3 (1 α ,25-(OH) 2 D 3 ) by CYP27B1 in the kidney and extrarenal tissues, and to nonactive metabolites by other cytochrome P450 enzymes. In addition, 25OHD 3 undergoes sulfation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD 3 -3- O -sulfate (25OHD 3 -S) and 25OHD 3 -3- O -glucuronide (25OHD 3 -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 25OHD 3 , and then converted to 1 α ,25-(OH) 2 D 3 , exerting local intestinal cellular effects, it is crucial to characterize enterohepatic transport mechanisms of 25OHD 3 -S and 25OHD 3 -G, and thereby understand and predict mechanisms of interindividual variability in mineral homeostasis. In the present study, with plasma membrane vesicle and cell-based transport studies, we showed that 25OHD 3 -G is a substrate of multidrug resistance proteins 2 and 3, OATP1B1, and OATP1B3, and that 25OHD 3 -S is probably a substrate of breast cancer resistance protein, 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 25OHD 3 conjugates, providing an alternative pathway of 25OHD 3 delivery to the intestinal tract, which could be critical for vitamin D receptor-dependent gene regulation in enterocytes. Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. The American Society for Pharmacology and Experimental Therapeutics (ASPET) 0090-9556 00909556 1521-009X 1521009X |
| shingle_catch_all_3 | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] Vitamin D 3 is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25-Hydroxyvitamin D 3 (25OHD 3 ), the most abundant circulating metabolite of vitamin D 3 , is further transformed to the biologically active metabolite 1 α ,25-dihydroxyvitamin D 3 (1 α ,25-(OH) 2 D 3 ) by CYP27B1 in the kidney and extrarenal tissues, and to nonactive metabolites by other cytochrome P450 enzymes. In addition, 25OHD 3 undergoes sulfation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD 3 -3- O -sulfate (25OHD 3 -S) and 25OHD 3 -3- O -glucuronide (25OHD 3 -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 25OHD 3 , and then converted to 1 α ,25-(OH) 2 D 3 , exerting local intestinal cellular effects, it is crucial to characterize enterohepatic transport mechanisms of 25OHD 3 -S and 25OHD 3 -G, and thereby understand and predict mechanisms of interindividual variability in mineral homeostasis. In the present study, with plasma membrane vesicle and cell-based transport studies, we showed that 25OHD 3 -G is a substrate of multidrug resistance proteins 2 and 3, OATP1B1, and OATP1B3, and that 25OHD 3 -S is probably a substrate of breast cancer resistance protein, 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 25OHD 3 conjugates, providing an alternative pathway of 25OHD 3 delivery to the intestinal tract, which could be critical for vitamin D receptor-dependent gene regulation in enterocytes. Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. The American Society for Pharmacology and Experimental Therapeutics (ASPET) 0090-9556 00909556 1521-009X 1521009X |
| shingle_catch_all_4 | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] Vitamin D 3 is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25-Hydroxyvitamin D 3 (25OHD 3 ), the most abundant circulating metabolite of vitamin D 3 , is further transformed to the biologically active metabolite 1 α ,25-dihydroxyvitamin D 3 (1 α ,25-(OH) 2 D 3 ) by CYP27B1 in the kidney and extrarenal tissues, and to nonactive metabolites by other cytochrome P450 enzymes. In addition, 25OHD 3 undergoes sulfation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD 3 -3- O -sulfate (25OHD 3 -S) and 25OHD 3 -3- O -glucuronide (25OHD 3 -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 25OHD 3 , and then converted to 1 α ,25-(OH) 2 D 3 , exerting local intestinal cellular effects, it is crucial to characterize enterohepatic transport mechanisms of 25OHD 3 -S and 25OHD 3 -G, and thereby understand and predict mechanisms of interindividual variability in mineral homeostasis. In the present study, with plasma membrane vesicle and cell-based transport studies, we showed that 25OHD 3 -G is a substrate of multidrug resistance proteins 2 and 3, OATP1B1, and OATP1B3, and that 25OHD 3 -S is probably a substrate of breast cancer resistance protein, 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 25OHD 3 conjugates, providing an alternative pathway of 25OHD 3 delivery to the intestinal tract, which could be critical for vitamin D receptor-dependent gene regulation in enterocytes. Gao, C., Liao, M. Z., Han, L. W., Thummel, K. E., Mao, Q. The American Society for Pharmacology and Experimental Therapeutics (ASPET) 0090-9556 00909556 1521-009X 1521009X |
| shingle_title_1 | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] |
| shingle_title_2 | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] |
| shingle_title_3 | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] |
| shingle_title_4 | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] |
| timestamp | 2025-06-30T23:34:11.917Z |
| titel | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] |
| titel_suche | Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract [Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction] |
| topic | V WW-YZ |
| uid | ipn_articles_6231109 |