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

Journal Article · Wed Dec 01 04:00:00 EST 1993 · Environmental Health Perspectives

DOI:https://doi.org/10.1289/ehp.93101s535· OSTI ID:585145

Ames, B N; Shigenaga, M K ^[1]; Gold, L S ^[2]

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1. Univ. of California, Berkeley, CA (United States)
2. Lawrence Berkeley National Lab., CA (United States)

DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 10{sup 6} 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 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).

• Sponsoring Organization: USDOE
• DOE Contract Number: AC03-76SF00098
• OSTI ID: 585145
• Journal Information: Environmental Health Perspectives, Journal Name: Environmental Health Perspectives Journal Issue: Suppl.5 Vol. 101; ISSN 0091-6765; ISSN EVHPAZ
• Country of Publication: United States
• Language: English

Related Subjects

56 BIOLOGY AND MEDICINE
APPLIED STUDIES
CARCINOGENESIS
CELL DIVISION
DNA REPAIR
GENETIC EFFECTS
MUTAGENESIS
NEOPLASMS
OXIDIZERS