Redox regulation of genes that protect against carcinogens

Most carcinogens require activation to electrophilic metabolites or species that generate reactive oxygen in order to initiate the tumorigenic process. These reactive intermediates can, in turn, be detoxified by endogenous enzyme systems that aid in the protection of cells from either toxic or mutagenic product formation. The levels of many of these enzymes are elevated by numerous compounds found in the diet, or by antioxidants. Recent evidence describes the mechanism for this induction of carcinogen detoxication enzymes to be regulated at the transcriptional level. Nuclear transcription factors bound to sites common among these carcinogen detoxification genes are activated by as yet unknown signal transduction pathways. The activity of these nuclear transcription factors are modulated by pro- and antioxidant reagents, suggesting that a redox-sensitive component governs the induction of enzymes involved in carcinogen metabolism. In this review, evidence for the redox regulation of the genes encoding carcinogen detoxication enzymes is presented. Evidence is also presented suggesting the participation of nuclear factor κB (NF-κB), mitogen-activated protein (MAP) kinase, and basic leucine zipper (bZIP) proteins and their activation pathways in this induction.