Dose Response Relationship in Anti-Stress Gene Regulatory Networks
Figure 12
Dose Response Curves of Electrophile X versus Stressor under Various Disrupted Conditions
(A) Effects of deregulation of Gclc, Gclm, Gs, and Gst genes by Nrf2. Deregulation was implemented by clamping mRNAs of respective genes at levels seen at the basal condition.
(B) Effects of lack of Nrf2 autoregulation and/or GST functioning as a homodimer. Removal of Nrf2 autoregulation was implemented similarly as in (A); de-dimerization of GST was implemented by replacing the quadratic term in Reaction 44 with a linear term that left GST concentration at the basal condition unchanged.
(C) Effects of product inhibition of GST-catalyzed reaction. For reduced GSX inhibition, Ki in Reaction 57 was increased to 850 μM from the default value 85 μM; for increased GSX inhibition, Ki was lowered to 8.5 μM. Deregulation and de-dimerization of MRP were similarly implemented as above for other enzymes.
(D) Effects of alteration in GSH levels via gene disruption or GCL activity inhibition. Genetic disruption of Gclc and Gclm genes was implemented by either setting the respective genes to half of the default values for heterozygous deficiency or to zero for homozygous deficiency. GCL activity inhibition was implemented by lowering kc in Reaction 54 to 2.5% of the default value.