Fig. 5

Activation of PXR-mediated gene expression. To represent drug-drug interactions, a kinetic model of PXR-mediated gene expression was generated, based upon Kolodkin et al. [61]. The nuclear receptor PXR is activated by the low affinity ligand Phenytoin (P), forming PXRL. This increases transcription of 20 PXR target genes, leading to increased concentrations of the encoded target proteins. Predicted fold-inductions of CYP3A mRNA and protein are consistent with data from Luo et al. [58]. n.d. = not determined. These target proteins are mapped to reactions within the Recon2 genome scale metabolic network, with their concentration setting reaction bounds within the network. This results in an altered metabolic capacity within the network, leading to increased estradiol (E) metabolism