DNA damage and repair

Many of the end points for tests described in this chapter, including gene mutation, chromosome damage, and oncogenicity, develop as a consequence of damage to or chemical modification of DNA. Most of these tests, however, also involve metabolic events that occur both prior to and subsequent to the modification of DNA. Some tests, however, use events at the DNA level as end points. One of these, the unscheduled synthesis of DNA in mammalian cells, is described in some detail the others are summarized briefly. 

Unscheduled DNA Synthesis in Mammalian Cells. The principle of this test is that it measures the repair that follows DNA damage and is thus a reflection of the damage itself. It depends on the autoradiographic measurement of the incorporation of tritiated thymidine into the nuclei of cells previously treated with the test chemical. 

The preferred cells are usually primary hepatocytes in cultures derived from adult male rats whose cells are dispersed and allowed to attach themselves to glass coverslips. 

This test has several advantages in that primary liver cells have considerable activation capacity and the test measures an event at the DNA level. It does not, however, distinguish between error-free repair and error-prone repair, the latter being itself a mutagenic process. Thus it cannot distinguish between events that might lead to toxic sequelae and those that do not. A modification of this test measures in vivo unscheduled DNA synthesis. In this modification animals are first treated in vivo, and primary hepatocytes are then prepared and treated as already described. 

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Mouse visible or eleetrophoretie specifie-locus tests Assays for skeletal and cataract mutations Cytogenetic analy.sis and heritable translocation assays DNA damage and repair in rodent germ cells Dominant lethal assay... 

Santocono, M, Zurria, M, Berrettini, M, Fedeli, D, and Falcioni, G, 2006. Influence of astaxanthin, zeaxanthin and lutein on DNA damage and repair in UVA-irradiated cells. J Photochem Photobiol B 85, 205-215. 

Collins, A. R. (2004). The COMET assay for DNA damage and repair. Molecular... 

A useful discussion of the metallation of pyrimidines is to be found in a more general review on metallation <06EJO1593>. A full issue of Chemical Reviews was concerned with DNA damage and repair, parts of which may be of interest relating to pyrimidine reactivity... 

Chopp, M., Chan, P. H., Hsu, C. Y., Cheung, M. E. and Jacobs, T. P. DNA damage and repair in central nervous system injury National Institute of Neurological Disorders and Stroke Workshop Summary. Stroke 27 363-369,1996. 

Assays for DNA Effects DNA damage and repair unscheduled DNA synthesis in vitro / ... 

Britt AB (1996) DNA damage and repair in plants. Annu Rev Plant Physiol Plant Mol Biol 47 75-100... 

Olive, P.L., Banath, J.P., and Durand, R.E., Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the "comet" assay, Radiat. Res., 122, 86, 1990. 

Sedelnikova OA, Pilch DR, Redon C, Bonner WM (2003) Histone H2AX in DNA damage and repair. Cancer Biol Ther 2 233-235... 

M. S. Kulkarni and K. L. Yielding, DNA damage and repair in epithelial (mucous) cells and crypt cells from isolated colon, Chem. Biol. Interact., 1985, 52(3), 311. 

Genetic Toxicology DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro (Original Guideline, adopted 23 October 1986)... 

Genetic toxicology DNA damage and repair, unscheduled DNA synthesis in mammahan cells in vitro 1986... 

B.18 DNA damage and repair Unscheduled DNA synthesis - Mammalian cells in vitro 1988... 

A positive result in the DNA damage and repair, unscheduled DNA synthesis in mammahan cells in vitro test indicates that a substance induces DNA damage in culmred mammahan somatic cells that can be repaired by UDS. UDS is described in more detail under the in vivo test. 

McGregor D, Anderson D. DNA damage and repair in mammalian cells in vitro and in vivo as indicators of exposure to cardnogens. In McGregor DB, Rice JM, Venitt S, eds. The Use of Short and Medium-... 

Barea, F. and Bonatto, D. (2008). Relationships among carbohydrate intermediate metabolites and DNA damage and repair in yeast from a systems biology perspective. Mutat. Res. 642,... 

Hamilton-Koch W, Snyder RD, Lavelle JM. 1986. Metal-induced DNA damage and repair in human diploid fibroblasts and Chinese hamster ovary cells. Chem Biol Interact 59 17-28. 

Schmitz-Hoerner, R. and Weissenboeck, G., Contribution of phenolic compounds to the UV-B screening capacity of developing barley primary leaves in relation to DNA damage and repair under elevated UV-B levels, Phytochemistry, 64, 243, 2003. 

It seems likely that a high proportion of all chemicals, whether synthetic or natural, would be carcinogens if administered in the standard rodent bioassay at the MTD, primarily because of the effects of high doses on cell death and division and DNA damage and repair.6 Without additional data about how a chemical causes cancer, the interpretation of a positive result in a rodent bioassay is highly uncertain. The induction of cancer could be the result of the high doses tested and have no predictive value about what might occur at lower doses. 

Snyder, R.D. Matheson, D.W. (1985) Nick translation—a new assay for monitoring DNA damage and repair in cultured human fibroblasts. Environ. Mutag., 1, 267-279... 

Vogel, E. W. Natarajan, A.T. (1995) DNA damage and repair in somatic and germ cells in vivo. 

Putative molecular interactions between glabrene and epigallocatechin gallate relating to DNA damage and repair in cells. 

Moller P, Vogel U, Pedersen A, Dragsted LO, Sandstrom B, Loft S. 2003. No effect of 600 grams fruit and vegetables per day on oxidative DNA damage and repair in healthy nonsmokers. Cancer Epidemiol Biomarkers Prev 12 1016-1022. 

Bianchini F, Hall J, Donato F, Cadet J (1996) Monitoring urinary excretion of 5-hydroxymethyluracil for assessment of oxidative DNA damage and repair. Biomarkers 1 178-184 Bienvenu C, Wagner JR, Cadet J (1996) Photosensitized oxidation of 5-methyl-2 -deoxycytidine by 2-methyl-1,4-naphthoquinone characterization of 5-(hydroperoxymethyl)-2 -deoxycytidine and stable methyl group oxidation products. J Am Chem Soc 118 11406-11411 Bothe E, Behrens G, Schulte-Frohlinde D (1977) Mechanism of the first order decay of 2-hydroxypro-pyl-2-peroxyl radicals and of O2 formation in aqueous solution. Z Naturforsch 32b 886-889 Bothe E, Deeble DJ, Lemaire DGE, Rashid R, Schuchmann MN, Schuchmann H-P, Schulte-Frohlinde D, Steenken S, von Sonntag C (1990) Pulse-radiolytic studies on the reactions of S04 with uracil derivatives. Radiat Phys Chem 36 149-154... 

Hwang J-T, Tallman KA, Greenberg MM (1999) The reactivity of the 2-deoxyribonolactone lesion in single-stranded DNA and its implication in reaction mechanisms of DNA damage and repair. Nucleic Acids Res 27 3805-3810... 

Schulte-Frohlinde D (1986) Comparison of mechanisms for DNA strand break formation by the direct and indirect effect of radiation. In Simic MG, Grossman L, Upton AD (eds) Mechanisms of DNA damage and repair basic life science Vol 38. Plenum Press, New York, pp 19-27 Schulte-Frohlinde D, Bothe E (1990) Determination of the constants of the Alper formula for singlestrand breaks from kinetic measurements on DNA in aqueous solution and comparison with data from cells. Int J Radiat Biol 58 603-611... 

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