DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.

Abstract

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 cells that appear to matter most in cancer, 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 nondividing 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 system 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 depends on the level of each defense, which in turn depends 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). Four endogenous processes leading to significant DNA damage are oxidation (1-3), methylation, deamination, and depurination (2). The importance of these processes is supported by the existence of specific DNA repair glycosylases for oxidative, methylated, and deaminated adducts and a repair system for apurinic sites that are produced by spontaneous depurination (3). Endogenous DNA Damage and MutagenesisDNA damage produced by oxidation appears to be the most significant endogenous damage (4). We estimate that the DNA hits per cell per day from endogenous oxidants are normally 105 in the rat and 104 in the human (5-7). These oxidative lesions are effectively but not perfectly repaired; the normal steady-state level of oxidative DNA lesions is about 106 per cell in the young rat and about twice this in the old rat (6,8). Oxidants are produced as byproducts of mitochondrial electron transport, various oxygen-utilizing enzyme system, peroxisomes, and other processes associated with normal aerobic metabolism...

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

“…Proliferation exposes DNA to the carcinogen and, thus, increases the likelihood of adduct formation. 29 Epithelial proliferation rates were not different between the p53 genotypes; consequently, altered AARGC could not have been an artefact of altered exposure of DNA to carcinogen. Some consider that the apoptotic response to carcinogen follows when there is a failure of DNA repair mechanisms associated with cell cycle arrest and subsequent entry of the cell into the S phase, where the adduct is recognised and triggers apoptosis.…”

The causes and prevention of cancer: gaining perspective.

“…Oxidative Damage and the Degenerative Diseases ofAging Aging and its degenerative diseases appear to be due in good part to the accumulation of oxidative damage to DNA and.other macromolecules (9). By-products of normal metabolism-superoxide, hydrogen peroxide, and hydroxyl radical-are the same oxidative mutagens produced by radiation (10).…”

“…By-products of normal metabolism-superoxide, hydrogen peroxide, and hydroxyl radical-are the same oxidative mutagens produced by radiation (10). Oxidative lesions in DNA accumulate with age, so that by the time a rat is old (2 years) it has about 1 million DNA lesions per cell, which is about twice the number in a young rat (9). Mutations also accumulate with age.…”

“…Adequate consumption of fruits and vegetables is associated with a lowered risk of degenerative diseases such as cancer, cardiovascular disease, cataracts, and brain and immune dysfunction (9). Nearly 200 studies in the epidemiological literature have been reviewed, and they show a consistent association between inadequate consumption of fruits and vegetables and cancer (19)(20)(21).…”

“…For hormonally related cancers, the protective effect of consuming fruits and vegetables is weaker and less consistent: for breast cancer the protective effect appears to be about 30% (16,19,22). Laboratory studies suggest that antioxidants such as vitamins C and E and carotenoids account for a good part of the beneficial effect of fruits and vegetables (9); however, epidemiologists have difficulty disentangling the effects of dietary intakes of the antioxidants from other important vitamins and ingredients in fruits and vegetables (23,24).…”