Severe hepatotoxicity of mithramycin therapy caused _by altered expression of hepatocellular bile transporters

Tristan M. Sissung, Phoebe A. Huang, Ralph J. Hauke, Edel M. McCrea, Cody J. Peer, Roberto H. Barbier, Jonathan D. Strope, Ariel M. Ley, Mary Zhang, Julie A. Hong, David Venzon, Jonathan P. Jackson, Kenneth R. Brouwer, Patrick Grohar, Jon Glod, Brigitte C. Widemann, Theo Heller, David S. Schrump, William D. Figg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P, 0.05) and were associated with $grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day 7, every 28 days; P, 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter a/b) in several cell lines [Huh7, HepaRG, HepaRG BSEP (2/2)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P, 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity (P, 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in ABCB11 (2/2) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P, 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses.

Original languageEnglish
Pages (from-to)158-167
Number of pages10
JournalMolecular Pharmacology
Issue number2
StatePublished - 2019
Externally publishedYes


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