TY - JOUR
T1 - Severe hepatotoxicity of mithramycin therapy caused _by altered expression of hepatocellular bile transporters
AU - Sissung, Tristan M.
AU - Huang, Phoebe A.
AU - Hauke, Ralph J.
AU - McCrea, Edel M.
AU - Peer, Cody J.
AU - Barbier, Roberto H.
AU - Strope, Jonathan D.
AU - Ley, Ariel M.
AU - Zhang, Mary
AU - Hong, Julie A.
AU - Venzon, David
AU - Jackson, Jonathan P.
AU - Brouwer, Kenneth R.
AU - Grohar, Patrick
AU - Glod, Jon
AU - Widemann, Brigitte C.
AU - Heller, Theo
AU - Schrump, David S.
AU - Figg, William D.
N1 - Publisher Copyright:
© 2019 American Society for Pharmacology and Experimental Therapy. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
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 (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.
UR - https://www.scopus.com/pages/publications/85069265654
U2 - 10.1124/mol.118.114827
DO - 10.1124/mol.118.114827
M3 - Article
C2 - 31175181
AN - SCOPUS:85069265654
SN - 0026-895X
VL - 96
SP - 158
EP - 167
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 2
ER -