Chemical Carcinogenesis Flashcards
What is a major difference between the pathology of an adenoma and a carcinoma?
Adenomas tend to be more benign than carcinomas (in most cases), although adenomas may impair physiological processes
True or false: A carcinogen is any substance that produces either benign or malignant tumors.
True, this is a regulatory perspective
What are the three steps of carcinogenesis?
initiation, promotion and progression
Carcinogens that act on the initiation stage of carcinogenesis tend to display which: threshold or non-threshold (linear) dose response?
these display a linear dose response, as these include genotoxins or mutagens that induce heritable changes in a cell line.
Carcinogens that act on the promotion stage of carcinogenesis tend to display which: threshold or non-threshold (linear) dose response?
these display a threshold dose response and tend to be organ specific
Which two stages of carcinogenesis tend to depend on mutagens or genotoxins and why?
Initiation and progression tend to rely on DNA damage to change the cell line and its regulation of normal growth and death
What are the two categories of DNA-reactive (genotoxic) carcinogens? What is an example chemical for each category?
Direct acting (parent) molecules, such as strong electrophiles (e.g. epoxides and halo ethers). Indirect acting genotoxins require metabolic activation before they can cause DNA damage. Aflatoxins and benzo[a]pyrenes require metabolic activation.
The polyaromatic hydrocarbon benzo[a]pyrene is a carcinogen. What is the MOA?
BaP is metabolized to a diol epoxide that creates DNA adducts in a specific oncogene.
Ethylene oxide and vinyl chloride are both examples of what class of genotoxic carcinogen?
They are both alkylating agents that generate strong electrophiles capable of forming adducts, leading to increased excision and DNA repair mechanisms.
What’s the MOA of carcinogenicity for aromatic amines and amides? What are two commons examples classes that cause exposure to either of these?
Amines and amides can form electrophiles and DNA adducts following metabolism or cleavage by gut flora to produce reactive electrophiles. Industrial dyes and high temp cooked foods are common sources.
How does cytotoxicity result in carcinogenesis?
Repeated cell death, likely due to metabolism of a substance, leads to tissue regeneration thereby increasing the likelihood of spontaneous mutation acquisition by a cell line.
What is the MOA for alpha 2 subunit (a2u)-globulin binding?
Chemicals that bind to a2u prevent complete lysosomal destruction of a2u in the tubules of the kidneys where it is reabsorbed. Incomplete destruction promotes lysosome accumulation. Excess lysosomes lead to cell necrosis and oxidative stress.
What is the speculated MOA of phenobarbital carcinogenicity?
It was originally believed to be cyp2b induction, but further research points to constitutive androstane receptor (CAR) activation that induces cyp2b and other genes that lead to carcinogenesis.
How does the Ames assay detect the induction of mutations/genotoxicity?
The Ames assay uses Salmonella typhimurium that lack a function gene for synthesizing histidine. Int he presence of a mutagen, the non-functional gene is “back mutated” to a functional gene and the bacteria grows additional colonies. This test detects direct genotoxic carcinogens, but not indirect. Addition of a metabolic source, like the S9 of liver homogenate, allows the basic testing of indirect carcinogens.
What are two eukaryotic cell tests used to detect genotoxic carcinogens?
Chinese hamster ovary (CHO) test for mutation to HGPRT (hypoxanthine-guanine phosophoribosyltransferase) to prevent 6-thioguanine toxicity. The other test is mouse lymphoma assay where genotoxic agents mutate the gene that metabolizes trifluorothymadine, thereby genotoxins prevent death of cells in culture.
