Fundamentals-of-Genetic-Toxicology-in-the-Pharmace在药物遗传毒理学基础.pptVIP

* * * * * * * * * * * * * * * * * * * * * Fundamentals of Genetic Toxicology in the Pharmaceutical Industry Prepared by: David Amacher, Ph.D, DABT What is Genetic Toxicology? Genetic Toxicology refers to the assessment of the deleterious effects of chemicals or physical agents on the hereditary material and related genetic processes of living cells. By altering the integrity and function of DNA1 at the gene or chromosomal level, the damage can lead to heritable mutations ultimately resulting in genetic disorders, congenital defects, or cancer. Targets of DNA damage include somatic cells (detrimental to the exposed individual), germinal cells (potentially heritable effects), and mitochondria (detrimental to the exposed individual progeny via maternal inheritance). 1 DNA = deoxyribonucleic acid * Deletions Rearrangements Breaks Genotoxic Classification Scheme * Microlesions Base-pair substitution mutations Frameshift mutations Macrolesions [cytologically visible] Numerical changes in chromosomes Stuructural changes in chromosomes Mutation [Qualitative change in 1 or a few nucleotide pairs] [Quantitative change in 1 or a few nucleotide pairs] Diagram from Bruswick, D.J. Alterations of germ cells leading to mutagenesis and their detection. Environ. Health Perspect. 24(1978):105-112. Mechanisms for Genetic Damage Genotoxic chemicals produce genetic damage at subtoxic levels. The types of DNA1 damage produced include: single- double-strand breaks, crosslinks between DNA bases and proteins, and chemical additions to the DNA bases (adducts). DNA replication itself can introduce errors via incorrect base substitution, a process that can be exacerbated by some genotoxic agents. 1 DNA = deoxyribonucleic acid * Types of Genetic Damage Base substitution: The replacement of the correct nucleotide by an incorrect one. A transition involves a change of a purine for a purine or a pyrimidine for a pyrimidine A transversion involves a change of a