T. M. Sissung, C. J. Peer, D. S. Schrump, W. D. Figg; National Cancer Institute, Bethesda, MD
BACKGROUND: Mithramycin (MITH) is under investigation for use in thoracic malignancies. Dose-limiting hepatotoxicity complicates therapy with MITH. Here, we show that hepatotoxicity is a function of single nucleotide polymorphisms (SNPs) in two apical hepatocellular transporters, ABCB4 (encoding PC-flopase) and ABCB11 (encoding BSEP). On this background, we hypothesized that MITH-induced hepatocellular damage results from SNP-dependent reduction in gene transcription.
METHODS: The Drug Metabolizing Enzymes and Transporters (DMET) genotyping array was used on germline DNA from 12 patients with various thoracic malignancies receiving MITH. After 3 daily doses of MITH, plateable human hepatocytes derived from an individual carrying variant SNPs were used to determine hepatotoxic MITH concentration, and study gene expression.
RESULTS: Grade 3-4 ALT and AST rises were observed in 8 of 12 patients that occurred following three daily administrations. Two SNPs in ABCB4 (rs2302387) and ABCB11 (rs4668115) were associated with LFT rises (OR(95%CI) = 153.0(2.6-9100); P=0.0020). Mithramycin plasma concentrations remained at sub-therapeutic levels, and pharmacokinetic parameters were not related to the LFT rises (P>0.061). MITH did not inhibit efflux of taurocholic acid; however, it reduced ABCB4 transcription in hepatocytes by approximately 30% (P=0.029) without affecting ABCB11. The 50% cytotoxic dose was 49.5nM.
CONCLUSION: Taken together, the data suggest MITH likely causes liver damage by reducing the expression of ABCB4, thereby disrupting bile flow. Further studies are underway in hepatocytes from patients with wild-type and heterozygous SNPs at both sites.