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. Author manuscript; available in PMC: 2020 Feb 27.
Published in final edited form as: Nat Chem Biol. 2016 Oct 10;12(12):1037–1045. doi: 10.1038/nchembio.2193

Figure 5. HCV activates PXR and induces CYP450 expression.

Figure 5

(a) Transcriptional regulatory analysis of drug metabolism showed significant enrichment in a number of transcription factors, including PXR and CAR, known regulators of CYP450 expression. Inferred regulators of drug metabolism are highlighted in blue on the full regulatory network (Supplementary Table 4). (b) Interaction network of the identified regulators HNF4α, PXR and CAR, and their differentially expressed targets. (c) qRT-PCR showed no change in the expression of PXR but a ninefold induction of CAR (P < 0.001, n = 3). PXR and CAR target genes CYP3A4 and CYP2C9 were upregulated eightfold and sixfold, respectively (P < 0.001, n = 3). (d) PXR GFP reporter activity was fivefold greater (P < 0.05, n = 3) in JC1-RFP-expressing Huh7.5.1 cells compared to Pol− controls. Inhibition of PXR with silibinin blocked its activation without affecting viral replication (Supplementary Fig. 8). Scale bars, 10 μm. (e) Functional assays showed a twofold induction of CYP3A4 activity (P < 0.005, n = 3) and a threefold induction of CYP2E1 activity (P = 0.013, n = 3) in HCV-infected primary hepatocytes. PXR-controlled CYP3A4 was completely blocked by silibinin. *P < 0.05; **P < 0.001; n refers to experimental replicates.

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