Connections Between Aryl Hydrocarbon Receptor Activation and Induction of Carbonyl Reductase Expression
Research Interest: My research involves the regulation of carbonyl reductase (CBR) activity. CBR mediates the two-electron reduction of the C-13 carbonyl group of the anthracyclines, which results in the production of metabolic intermediates that are cardiotoxic. We are currently investigating strategies to regulate CBR expression and/or activity, which could lead to decreased cardiotoxicity associated with anthracycline treatment. Recent evidence links activation of the aryl hydrocarbon receptor (AhR), a soluble, ligand-activated transcription factor, to the induction of CBR. We hypothesized that inhibition of AhR signaling using resveratrol, a documented AhR antagonist, would decrease CBR protein expression. We also hypothesized that anthracyline induces CBR protein expression by a mechanism that involves AhR activation. My work includes growing rat 5L hepatoma cells and treating them with antracycline, as well as AhR agonists and antagonists. Western blotting was done to detect Cyp1a1 protein expression, which is an AhR-regulated target gene that is used to measure AhR activation. Results from these studies are expected to implicate the AhR in the anthracycline-mediated induction of CBR. Moreover, they will likely shed light on the possibility of using AhR antagonists to decrease the cardiotoxicity associated with anthracycline treatment. (NIH Grant # P20 RR016454 and Merck Foundation).