Genotoxicity
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Bacterial Reverse Mutation Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . L5178Y tk +/– Mouse Lymphoma Test . . . . . . . . . . . . . . . . Micronucleus Test in vitro . . . . . . Micronucleus Test in vivo. . . . . . . Mammalian Chromosome Aberration Test in vitro . . . . . . . . Mammalian Chromosome Aberration Test in vivo . . . . . . . . . Unscheduled DNA Synthesis Test with Mammalian Liver Cells in vitro . . . . . . . . . . . . . . . . . . . Unscheduled DNA Synthesis Test with Mammalian Liver Cells in vivo . . . . . . . . . . . . . . . . . . . .
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INTRODUCTION
The task of Genetic Toxicology is to use recognized test methods in order to identify the so-called genotoxic or mutagenic potential of pharmaceuticals and chemicals. The genotoxic or mutagenic potential is what we call the potential health risk of a substance with respect to its ability to cause cell mutations. Substances with this potential are known as mutagens, and genotoxicity studies – also called mutagenicity studies – help identify such substances. Early warnings that a possible new drug may have a genotoxic effect are of immense importance for drug development. If a potential new drug is proven to have a genotoxic potential, this generally leads to termination of development of that drug, thereby preventing human exposure to drugs with mutagenic effects. Numerous test methods are available for assessing the genotoxic potential of substances. There are essentially three main categories of genotoxic damage that can be caused by a substance: • Gene mutations • Chromosome aberrations and genome mutations • DNA damage and DNA repair.
Gene mutations include base pair substitutions and frameshift mutations, where base pair substitutions arise from the substitution of one or several base pairs in the DNA, and frameshift mutations arise from an insertion or deletion involving a number of base pairs that is not a multiple of three and consequently disrupts the triplet reading frame, usually leading to the creation of a premature termination (stop) codon and resulting in a truncated protein product. Chromosomal aberrations include both numerical and structural aberrations. Numerical aberrations are changes in the number of chromosomes of the normal number characteristic of the animals utilized (aneugenicity). Structural aberrations are classified into two types, chromosome or chromatid aberrations (clastogenicity). Chromosomal mutations and related events are the cause of many human genetic diseases and there is evidence that chromosomal mutations and related events are involved in cancer development. DNA damage can happen in several ways. For example, energy production in cells can produce toxic molecules, such as the so-called free radicals. They can react with the bases in the DNA and modify them, thus preventing the genetic code from being used properly. Those DNA damages then need to be repaired. All cells have evolved a system of recognizi
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