Figure 8:

Scheme of the dependence of nitroreduction of 1-NP on NRF2 and AKR1C1-1C3 in a system of constitutive NRF2 versus inducible NRF2. We found that AKR1C1-1C3 inhibitors reduce 1-AP production in each cell type, and effects of flufenamic acid, salicylic acid, and ursodeoxycholate were particularly potent in HBEC3-KT cells, each causing over 70% inhibition to support that AKR1Cs are the major 1-NP nitroreductases in HBEC3-KT cells. Whereas NRF2 activators were effective at increasing 1-AP production in HBEC3-KT cells that have inducible NRF2, NRF2 inhibitors were effective at decreasing 1-AP production in A549 cells that have constitutively active NRF2. By contrast, we did not find POR inhibitors, a NQO1 inhibitor, or a XO inhibitor to reduce 1-AP production in either cell type. Our results with rotenone imply a role of ROS or mitochondrial nitroreductases in the nitroreduction of 1-NP, particularly for A549 cells where AKR1C inhibition could not explain all contribution to 1-NP nitroreduction.