The role of oxidative stress in environmental carcinogenesis

Radicals are molecules with one or more unpaired electrons on an atom (either carbon, nitrogen, or oxygen). Radicals interact with non-radicals creating new radicals by a chain reaction. Oxygen from normal mitochondrial metabolism results in the formation of reactive oxygen species (ROS) by the successive addition to electrons to oxygen catalyzed by cytochrome oxidase. Oxidative reactions play an important role in biology as they provide the energy required for various functions and defense against various diseases. Several enzymatic/radical steps and the availability of transition metals, such as iron and copper, result in the production of the highly reactive hydroxyl radical in a Fenton-type reaction. Nitric oxide produced by macrophages reacts with superoxide radicals leading eventually to the production of hydroxyl radicals. Hydroxyl radical and other reactive secondary intermediates have the capacity to cause DNA oxidation or deamination, nitrosation of protein, and peroxidation of lipids. Oxidative stress arises either from overproduction of ROS when further induced by external environmental carcinogens, or from the deficiency of body's antioxidant defense or repair mechanisms. Chronic inflammation contributes to oxidative stress and to cancer induction. The cellular components mediating radical generation include the endoplasmic reticulum, mitochondria and cytosol, with other components present in membrane and DNA. Several carcinogens present in inhaled smoke, polluted air, radiation, ingested foods and drinks, pesticides and metals are capable of producing oxidative stress, partially through generation of ROS during metabolism. Oxidative damage to DNA results in both structural and base damage. Structural damage include helical distortion, single-strand breaks, double-strand breaks, intrastrand cross links and chromosomal aberrations. These lesions ultimately result in genomic instability which favors tumor formation. Chemical damage to DNA results in many base modifications, the most ubiquitous of which is 8- hydroxy-2'-deoxyguanosine (8-OH-dG). This modified nucleoside is excreted in the urine and can also be isolated from lymphocytes; it can thus serve as a biomarker for the extent of oxidative DNA damage. ROS are involved in all stages of carcinogenesis (initiation, promotion and progression). Stress alters signaling pathways that regulate the transcription of genes involved in cell growth and proliferation, leading to cascades of biological reactions such as expression of oncogenes, inactivation of tumor suppressor genes, and stimulation of transcription factors and cytokines, all of which ultimately result in tumor initiation, clonal expansion and cancer progression. Cells have the ability to repair ROS-induced damage by either general repair mechanisms such as nuclear excision repair, or mismatch DNA repair, or by repair of specific lesions (i.e., base excision repair) via enzymes such as DNA glycosylases and apurinic/apyrimidinic endonucleases, etc. Cellular oxidative defence mechanisms encompassing multitiered defenses are directed against several aspects of the antioxidant challenge and they serve complementary functions within the context of a multitiered oxidative challenge. Enzyme-directed antioxidant defenses (e.g., superoxide dismutase, catalase and glutathione peroxidase) are generally directed against the primordial initiator superoxide and the less reactive secondary mediators such as hydrogen peroxide and organic hydroperoxides. Small molecule chain- breaking antioxidants such as vitamins, plant polyphenols, bilirubin and uric acid, act mainly against peroxyl radicals. Although there is considerable interest in the role of the diet in protecting against radical-induced environmental carcinogenesis, increased ingestion of antioxidants is currently a subject of ongoing controversy. The best strategy currently available to protect against ROS-induced carcinogenesis is to reduce endogenous and exogenous sources of oxygen-generated stress.