Ah receptor- and Nrf2-gene battery members: modulators of quinone-mediated oxidative and endoplasmic reticulum stress

Quinones are ubiquitously present in mammals and their environment. They are involved in physiologic functions such as electron transport but are also toxic compounds. In particular, quinone-quinol redox cycles may lead to oxidative stress, and arylating quinones have been demonstrated to activate endoplasmic reticulum (ER) stress. To detoxify quinones coordinately regulated Ah receptor and Nrf2 gene batteries evolved. Two pathways are emphasized: (i) glutathione S-transferases, and (ii) NAD(P)H:quinone oxidoreductases NQO1 and NQO2 acting together with UDP-glucuronosyltransferases and sulfotransferases. Coupling between these enzymes may prevent oxidative and ER stress in a tissue-dependent manner, as discussed using benzo[a]pyrene detoxification in enterocytes, catecholestrogen metabolism in breast tissue and endometrium, and aminochromes in neurones and astrocytes. Possible consequences of chronic ER stress such as apoptosis and inflammation as well as therapeutic possibilities of modulating Ah receptor and Nrf2 are discussed. In conclusion, tight coupling of Ah receptor- and Nrf2-regulated enzymes may prevent quinone-mediated oxidative and ER stress.