PT  - JOURNAL ARTICLE
AU  - Tristan M. Sissung
AU  - Phoebe A. Huang
AU  - Ralph J Hauke
AU  - Edel M. McCrea
AU  - Cody J. Peer
AU  - Roberto H. Barbier
AU  - Jonathan D. Strope
AU  - Ariel M. Ley
AU  - Mary Zhang
AU  - Julie A. Hong
AU  - David Venzon
AU  - Jonathan P. Jackson
AU  - Kenneth R. Brouwer
AU  - Patrick Grohar
AU  - Jon Glod
AU  - Brigitte C. Widemann
AU  - Theo Heller
AU  - David S. Schrump
AU  - William D Figg
TI  - Severe Hepatotoxicity of Mithramycin Therapy Caused by Altering Expression of Hepatocellular Bile Transporters
AID  - 10.1124/mol.118.114827
DP  - 2019 Jan 01
TA  - Molecular Pharmacology
PG  - mol.118.114827
4099  - http://molpharm.aspetjournals.org/content/early/2019/06/07/mol.118.114827.short
4100  - http://molpharm.aspetjournals.org/content/early/2019/06/07/mol.118.114827.full
AB  - 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 (MDR3) rs2302387 and ABCB11 (BSEP) rs4668115 reduce transporter expression (P<0.05) and were associated with mean ≥ Grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25mcg/kg, 6hr/infusion, qdx7, 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, NTCP, OST mean α/β) in several cell lines (Huh7, HepaRG, HepaRG BSEP (-/-)) 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 CDCA- and GW4046-induced FXR-GAL4 luciferase reporter activity (P<0.001). Mithramycin promoted GCDC-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P<0.01). Mithramycin is an 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.SIGNIFICANCE STATEMENT The present study characterizes a mechanism of hepatotoxicity in which an FXR inhibitor causes deregulation of bile homeostasis in liver, which is currently the rationale for a genotype-directed clinical trial using mithramycin (NCT01624090).