Ames, B.N., Shigenaga, M.K., and Gold, L.S. DNA lesions, inducible DNA repair, and cell division: Three key factors in mutagenesis and carcinogenesis. Environmental Health Perspectives 101 (Suppl. 5): 35-44 (1993).
DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 106 oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system, and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent, whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in those cells that matter. Those cells that appear to matter most for cancer are the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases mutation and therefore cancer. There is little cancer from non-dividing cells. Endogenous cell division rates can be influenced by hormone levels, decreased by calorie restriction, or increased by high doses of chemicals. If both the rate of DNA lesions and cell division are increased then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example by high doses of a mutagen that also increases mitogenesis through cell killing. The defense systems against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible, and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult is dependent on the level of each defense, which in turn is dependent on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants).
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