Nitroreduction: A process of metabolic activation that involves aldo-keto reductases, NRF2, autophagy, and microbiota

Exposure to nitro-containing compounds is a potential risk factor for mutagenesis leading to various cancers. Understanding the biological chemistry for the biotransformation and metabolism of nitro-containing compounds is critical for assessing and countering the health risks. A major pathway for the biological metabolism of nitro-containing compounds is nitroreduction, the six-electron reduction of a nitro group to generate an amine. Mechanisms associated with mutagenicity that arise from nitroreduction include the formation of covalent DNA adducts derived from the hydroxylamino intermediate and the generation of reactive oxygen species (ROS) from the oxidation of reduced metabolites. In the seminar, I will discuss the role of human aldo-keto reductases (AKRs) 1C1-1C3 in the nitroreduction of 1-nitropyrene (1-NP) and 1,8-dinitropyrene (1,8-DNP), two nitroarenes that are found in diesel exhaust. Because AKR1C1-1C3 are downstream target genes of the transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2), my presentation will also cover how the nitroreduction of 1-NP and 1,8-DNP depends on expression levels of NRF2 in human lung cells. I will then briefly discuss mechanisms, some involving NRF2, by which the catabolic process of autophagy may regulate the ability of cells to catalyze nitroreduction. My presentation will conclude with a brief overview of how some bacteria may use host autophagy and NRF2 to catalyze nitroreduction. In totality, the presentation will advance understanding on the extent to which AKRs, NRF2, autophagy, and microbiota may be considered oncogenic in the context of nitroreduction.