Abstract
The bile salt export pump (BSEP, ABCB11) is predominantly responsible for the efflux of bile salts, and disruption of BSEP function is often associated with altered hepatic homeostasis of bile acids and cholestatic liver injury. Accumulating evidence suggests that many drugs can cause cholestasis through interaction with hepatic transporters. To date, a relatively strong association between drug-induced cholestasis and attenuated BSEP activity has been proposed. However, whether repression of BSEP transcription would contribute to drug-induced cholestasis is largely unknown. In this study, we selected 30 drugs previously reported as BSEP inhibitors to evaluate their effects on BSEP expression, farnesoid X receptor (FXR) activation, and correlations to clinically reported liver toxicity. Our results indicate that of the 30 BSEP inhibitors, five exhibited potent repression of BSEP expression (≥60% repression), ten were moderate repressors (20–60% repression), whereas others had negligible effects (≤20% repression). Of importance, two drugs (troglitazone and benzbromarone), previously withdrawn from the market because of liver injury, are among the potent repressors. Further investigation of the five potent repressors revealed that transcriptional repression of BSEP by lopinavir and troglitazone may occur through their interaction with FXR, whereas others are via FXR-independent yet unidentified pathways. Our data suggest that in addition to functional inhibition, repression of BSEP expression may play an important role in drug-induced cholestatic liver toxicity. Thus, a combination of the two would reveal a more accurate prediction of drug-induced cholestasis than does either repression or inhibition alone.
Footnotes
- Received August 12, 2013.
- Accepted December 11, 2013.
This work was supported by the US Food and Drug Administration [Award U01FD004320] and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK061652]. The manuscript reflects the views of the authors and should not be construed to represent FDA’s views or policies.
↵This article has supplemental material available at dmd.aspetjournals.org.
- U.S. Government work not protected by U.S. copyright
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