chemical_models

chemical_models - Hepatocarcinogenesis: chemical models...

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Unformatted text preview: Hepatocarcinogenesis: chemical models Introduction Earliest observations that human exposure to certain chemicals is related to an increased incidence of cancer John Hill 1761 Nasal cancer in snuff users Sir Percival Pott 1775 Scrotal cancer in chimney sweeps Soot and coal tar Experimental chemical carcinogenesis Yamagiwa and Ichikawa 1918 Multiple applications of coal tar to rabbit ears produced skin carcinomas First demonstration that a chemical could produce cancer in an animal Confirmed Potts initial observation and linked human epidemiology and animal carcinogenicity Somatic mutation theory Theodor Boveri 1914 Concept that cancer involves an alteration in the genetic material of the somatic cell Chromosome abnormalities Furth and Kahn 1934 Isolated single cell clones from a tumor and showed that injection into a healthy host could reproduce disease Cancer = stable heritable cellular alteration Chemical carcinogenesis James and Elizabeth Miller 1950s Observed that a wide variety of structurally diverse chemicals could produce cancer in animals Proposed that all of these chemicals require metabolic activation to electrophilic reactive intermediates Covalently bind to nucleophilic centers on proteins, RNA, or DNA Electrophilic theory of chemical carcinogenesis Evidence for genetic mechanisms 1) Cancer is a heritable stable change 2) Tumors are generally clonal in nature 3) Many carcinogens are metabolized to electrophilic intermediates that covalently bind to DNA 4) Many carcinogens are also mutagens 5) Many cancers display chromosomal abnormalities 6) Transformed phenotype can be transferred from a tumor cell to a non-tumor cell by DNA transfection Genotoxic agents Direct acting carcinogens N-methyl-N-nitrosourea (MNU) N-methyl-N-nitro-N-nitrosoguanidine (MNNG) Indirect acting carcinogens Dimethylnitrosamine (DMN) Benzo[a]pyrene Radiation Inorganic agents Image removed due to copyright reasons.Image removed due to copyright reasons....
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chemical_models - Hepatocarcinogenesis: chemical models...

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