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Gene expression data from primary human hepatocytes treated with GGF2 for 6, 24, or 72 h or 24 h with a 48 h washout.

ABSTRACT: GGF2 is a recombinant human neuregulin-1β in development for chronic heart failure. Phase 1 clinical trials of GGF2 were put on hold when transient elevations in serum aminotransferases and total bilirubin were observed in 2 of 43 subjects receiving GGF2. However, aminotransferase elevations were modest and not typical of liver injury sufficient to result in elevated serum bilirubin. Several translational approaches were used to understand the liver response associated with GGF2. Gene expression profiling was performed in sandwich-cultured human hepatocytes treated with GGF2 (0-3760 pM) for up to 72 h. Prior cytochrome P450 induction studies had unexpectedly demonstrated suppression of cytochrome P450 3A4 (CYP3A4) mRNA in primary human hepatocytes exposed to GGF2 for 24 h. Although no direct cytotoxicity was observed in response to GGF2, the suppression of CYP3A4 transcript levels in primary hepatocyte cultures had a temporal profile consistent with the transient bilirubin elevations observed in vivo. While downregulation of CYP3A4 alone should not influence serum bilirubin levels, it was reasoned that concomitant alterations in the expression of other liver proteins, such as those involved in bilirubin transport, could help to explain the liver response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99926 | GEO | 2017/06/13

SECONDARY ACCESSION(S): PRJNA390142

REPOSITORIES: GEO

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Project description:In drug development, a system for predicting drug metabolism and drug-induced toxicity is necessary to ensure drug safety. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is an important drug-metabolizing enzyme expressed in the liver and small intestine, and predicting CYP3A4-mediated drug metabolism and drug-induced toxicity is essential. We previously developed procedures to differentiate human induced pluripotent stem (iPS) cells into hepatocyte-like cells (HLCs) or intestinal epithelial-like cells (IECs) with a fetal phenotype as well as a highly efficient genome editing technology that could enhance the homologous recombination efficiency at any locus, including CYP3A4. By using human iPS cells and our genome editing technology, we generated CYP3A4-knockout (KO) iPS cell-derived HLCs and IECs for the evaluation of CYP3A4-mediated drug metabolism and drug-induced toxicity. CYP3A4 deficiency did not affect pluripotency and hepatic and intestinal differentiation capacities, and CYP3A4 activity was entirely eradicated by CYP3A4 KO. Off-target effects (e.g., inhibition of bile acid excretion) were hardly observed in CYP3A4-KO cells but were observed in CYP3A4 inhibitor-treated (e.g., ketoconazole) cells. To evaluate whether drug-induced hepatotoxicity and enterotoxicity could be predicted using our model, we exposed CYP3A4-KO HLCs and IECs to acetaminophen, amiodarone, desipramine, leflunomide, tacrine, and tolcapone and confirmed that these cells could predict CYP3A4-mediated toxicity. Finally, we examined whether the therapeutic effects of an anti-hepatitis C virus (HCV) drug metabolized by CYP3A4 would be predicted using our model. CYP3A4-KO HLCs were treated with asunaprevir (antiviral drug metabolized by CYP3A4) after HCV infection, and the anti-viral effect was indeed strengthened by CYP3A4 KO. Conclusion: We succeeded in generating a novel evaluation system for prediction of CYP3A4-mediated drug metabolism and drug-induced toxicity.