3 carcinogenesis II Flashcards
what are the categories of carcinogens?
-genotoxic carcinogens
-nongenotoxic (epigenetic) carcinogens
-cocarcinogens
-solid state carcinogens
-complete carcinogens
-metals
what are genotoxic carcinogens?
-although some xenobiotics are direct-acting, most carcinogenic chemicals are inactive (called procarcinogens or precarcinogens) and must be bioactivated to yield reactive metabolites such as epoxides (called ultimate carcinogens)
-glutathione provides electron for electrophile
what is often involved in genotoxic carcinogens?
-activated proto-oncogenes (e.g. Ras)
-inactivated tumor suppressor genes (e.g. p53)
what is an example of a procarcinogen, proximate carcinogen, and ultimate carcinogen?
benzo(a)pyrene (BaP)
-after 1st CYP, it is very unstable and therefore has very short half life
-after 2nd CYP, it is a much more stable metabolite so it has a much longer half-life (time to bind DNA)
certain ________________ such as __________ are potent carcinogens that bind covalently to DNA?
polycycle aromatic hydrocarbons (PAHs) such as BaP
-adduct=covalently bonded so irreversible unless repaired
what are nongenotoxic carcinogens?
-“promoters of mitosis and/or inhibitors of apoptosis”
-do not damage DNA
-also referred to as epigenetic carcinogens because DNA methylation is likely involved (hypomethylation=enhanced gene expression, hypermethylation=blocked gene expression)
what are the examples of nongenotoxic carcinogens?
-xenobiotic mitogens (stimulates mitosis) (e.g. DDT, PCBs, Cd)
-endogenous mitogens (e.g. estrogens, androgens, growth factors)
-xenobiotics that cause sustained cell injury (e.g. chloroform)
what is the summary graph of genotoxic carcinogens?
what is the summary graph of nongenotoxic carcinogens?
what is the summary of characteristics of genotoxic vs nongenotoxic carcinogens?
what are cocarcinogens?
-are not carcinogenic themselves, but increase (potentiate) the effect of a carcinogen, mainly through effects on ADME
-e.g. a non-carcinogenic xeno that induces a CYP enzymes involved in bioactivation of procarcinogen (e.g. ethanol induces CYP2E1)
what are solid state carcinogens?
-e.g. asbestos, silica (quartz dust)
-both are group 1 carcinogens (known human carcinogens)
-precise mechanisms unclear, but lung cancer is a result of continuous irritation, oxidative stress and/or excessive fibrosis in alveoli
-Fe in asbestos stimulates conversion of H2O2 to HO (very bad radical)
what are complete carcinogens?
-xenobiotic mixtures that consist of chemicals that are involved in all 3 stages (initiation, promotion and progression) of cancer
-e.g. tobacco smoke
-e.g. ethanol (a group 1 carcinogen responsible for 3.5% of cancer deaths in USE)
-to make matters worse, exposure to both tobacco smoke and ethanol causes a synergistic effect on carcinogenicity
what are metals?
-e.g. arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr), and nickel (Ni) are known (group 1) carcinogens in humans
-carcinogenic mechanisms unclear and complex; may be either genotoxic and/or nongenotoxic
-likely involve ROS production and oxidative stress as a key mechanism
