AI Article Synopsis
- The bile salt export pump (BSEP) is crucial for clearing bile acids from the liver, and this study investigates how certain drugs, like metformin and tamoxifen, can suppress BSEP expression, affecting bile acid movement.
- The research involved examining the effects of metformin on BSEP activity in human liver cells and found that metformin lowers BSEP expression over time without directly inhibiting its function.
- The findings indicate that BSEP repression could lead to drug-induced cholestasis, suggesting that targeting gene repression may be an important area for understanding and managing this condition in response to certain medications.
Article Abstract
Purpose: The bile salt export pump (BSEP), a key player in hepatic bile acid clearance, has been the center of research on drug-induced cholestasis. However, such studies focus primarily on the direct inhibition of BSEP, often overlooking the potential impact of transcriptional repression. This work aims to explore the disruption of bile acid efflux caused by drug-induced BSEP repression.
Methods: BSEP activity was analyzed in human primary hepatocytes (HPH) using a traditional biliary-clearance experiment and a modified efflux assay, which includes a 72-h pretreatment prior to efflux measurement. Relative mRNA and protein expressions were examined by RT-PCR and Western blotting, respectively.
Results: Metformin concentration-dependently repressed BSEP expression in HPH. Although metformin did not directly inhibit BSEP activity, longer metformin exposure reduced BSEP transport function in HPH by down-regulating BSEP expression. BSEP repression by metformin was found to be AMP-activated protein kinase-independent. Additional screening of 10 reported cholestatic non-BSEP inhibitors revealed that the anti-cancer drug tamoxifen also markedly repressed BSEP expression and reduced BSEP activity in HPH.
Conclusions: Repression of BSEP alone is sufficient to disrupt hepatic bile acid efflux. Metformin and tamoxifen appear to be prototypes of a class of BSEP repressors that may cause drug-induced cholestasis through gene repression instead of direct BSEP inhibition.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357855 | PMC |
| http://dx.doi.org/10.1007/s11095-019-2753-x | DOI Listing |
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