Regulation of genes encoding NAD(P)H : quinone oxidoreductases

NAD(P)H:quinone oxidoreductase (NQO1) and NRH:quinone oxidoreductase (NQO2) are flavoproteins that catalyze two-electron reduction and detoxification of quinones and its derivatives. This leads to the protection of cells agai nst redox cycling, oxidative stress, and neoplasia. NQO1 is expressed ubiqu itously in all the tissues. However, the level of expression varied among t he human tissues. NQO1 gene is expressed at higher levels in several tumor tissue types, including liver and colon, as compared to normal tissues of s imilar origin. NQO1 gene expression is coordinately induced with other deto xifying enzyme genes in response to xenobiotics, antioxidants, oxidants, he avy metals, and radiations. Deletion mutagenesis in the NQO1 gene promoter identified several cis-elements including antioxidant response element (ARE ), a basal element, and AP-2 element. ARE elements have also been found in the promoter regions of other detoxifying enzyme genes including glutathion e S-transferases. ARE is essentially required for expression and coordinate d induction of NQO1 and other detoxifying enzyme genes. Nuclear transcripti on factors Nrf2 and c-Jun bind to the ARE and activate the gene expression. The binding of Nrf2 + c-Jun to the ARE required unknown cytosolic factor(s ). In addition to Nrf2 and c-Jun, other nuclear transcription factors inclu ding Nrf1, Jun-B, and Jun-D also bind to the ARE: and regulate expression a nd induction of NQO1 gene. A hypothetical model is presented based on the a vailable information on ARE-mediated regulation of detoxifying enzyme genes . Briefly, the Nrf2 is retained in the cytosplasm by a repressor protein Ke ap1 in untreated normal cells. The treatment of cells with xenobiotics and antioxidants leads to the activation of unknown cytosolic factor(s) that ca talyze modification of Nrf2 and/or Keap1. The modification follows dissocia tion of Nrf2 and Keap1. The free Nrf2 translocates in the nucleus. Nrf2 in the nucleus heterodimerizes with c-Jun and binds to the ARE resulting in th e induction of NQO1 and other ARE-regulated genes expression. The identity of cytosolic factor(s) remains unknown. (C) 2000 Elsevier Science Inc.