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Redox regulation of genes that protect against carcinogens
T Primiano1, T R Sutter, T W Kensler
1Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Abstract:
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 and 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 detoxication 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 kappa B (NF-kappa B), mitogen-activated protein (MAP) kinase, and basic leucine zipper (bZIP) proteins and their activation pathways in this induction.
Insights
Most carcinogens need activation to cause cancer, but the body has enzyme systems to detoxify them. Diet compounds and antioxidants can boost these enzymes, suggesting a redox-sensitive mechanism regulates this protective response.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Carcinogens initiate tumorigenesis via reactive metabolites.
- Endogenous enzyme systems detoxify reactive intermediates, protecting cells from damage.
- Dietary compounds and antioxidants can elevate carcinogen-detoxifying enzyme levels.
Purpose of the Study:
- To review evidence for redox regulation of carcinogen detoxication enzymes.
- To explore the transcriptional regulation of these genes.
- To identify key signaling pathways involved in enzyme induction.
Main Methods:
- Literature review of studies on carcinogen metabolism and enzyme induction.
- Analysis of evidence for transcriptional regulation by nuclear factors.
- Examination of the role of redox signaling in gene induction.
Main Results:
- Carcinogen detoxication enzyme induction is regulated at the transcriptional level.
- Redox-sensitive pathways modulate the activity of nuclear transcription factors.
- Nuclear Factor kappa B (NF-kappa B), MAP kinase, and bZIP proteins are implicated in this induction.
Conclusions:
- The induction of carcinogen detoxication enzymes is governed by a redox-sensitive mechanism.
- Transcriptional regulation involving specific transcription factors plays a key role.
- Understanding these pathways can inform strategies for cancer prevention.