NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase (NQO2) are flavoproteins that catalyze the metabolic detoxification of quinones and their derivatives to hydroquinones, using either NADH or NADPH as the electron donor. This protects cells against quinone-induced oxidative stress, cytotoxicity, and mutagenicity. Many tumors overexpress NQO1, which is an obligate two-electron reductase that deactivates toxins and activates bioreductive anticancer drugs. NQO1, a 274 amino acid protein, is ubiquitously expressed, but the expression level varies among tissues. NQO1 gene expression is coordinately induced in response to xenobiotics, antioxidants, heavy metals and radiation. The antioxidant response element (ARE) in the NQO1 gene promoter is essential for expression and coordinated induction of NQO1. ARE activation by tert-butylhydroquinone is dependent on PI3-kinase, which lies upstream of Nrf2. Nrf2, c-Jun, Nrf1, Jun-B and Jun-D bind to the ARE and regulate expression and induction of NQO1 gene. Maf-Maf homodimers and possibly Maf-Nrf2 heterodimers play a role in negative regulation of ARE-mediated transcription, but Maf-Nrf1 heterodimers fail to bind with the NQO1 gene ARE and do not repress NQO1 transcription.
