4 - Chemical Carcinogenesis Flashcards
What are direct carcinogens?
able to directly act on DNA alone right away | ie: adducts
What are indirect carcinogens?
carcinogen needs to be enzymatically broken down = intermediates/byproducts directly act on DNA | carcinogen itself doesn’t directly act on DNA, its the byproducts
How can compounds produced from industrial plants cause us cancer?
dumping those hydrophobic compounds in water »_space;> compounds get stuck on fish gills »_space;> we eat the fish = we now have the hydrophobic compounds
What are DNA intercalating agents?
carcinogens that intercalate between base pairs and disrupt DNA synthesis | ie: acridine orange and PCBs
What is synergy? (chemical interaction)
the effect of 2 or more chemicals taken together = greater than the sum of their separate effects
What is additive? (chemical interaction)
chemical A effect + chemical B effect = additive effect of chemicals A and B
Are most carcinogens lipophilic? What is lipophilic and what do these carcinogens require to be effective?
most carcinogens = lipophilic = hydrophobic = need to be metabolized to take effect
What are the 4 pathways our bodies eliminate toxin?
renal | hepatic | intestinal | local neutralization
What happens if the carcinogen is not eliminated from the body?
accumulated in the tissues
What is renal clearance?
carcinogen/toxin clearance via kidneys
What is the role of the kidneys in toxin elimination?
filters out blood »_space;> gets rid of hydrophilic chemicals (water soluble) »_space;> excreted as pee
What is hepatic clearance?
carcinogen/toxin clearance via liver
What is the role of the liver in toxin elimination?
filters out blood »_space;> gets rid of lipophilic chemicals (water-insoluble/fat-soluble) »_space;> excreted as poop
What is the goal of carcinogen elimination?
take carcinogen through hepatic clearance or make them water soluble for renal clearance
What are the phases of carcinogen elimination?
Phase I and Phase II
What is Phase I of carcinogen elimination? What is the enzyme(s) involved?
activates carcinogen | cytochrome P450 (CYP450)
What is the function of CYP450?
helps detoxify carcinogen by trying to make it water soluble
What is Phase II of carcinogen elimination? What is the enzyme involved?
detoxify carcinogen via conjugation | glutathione S-transferase (GST1) (and others too)
What activates CYP450?
reductase
What is the dangerous part of Phase I in carcinogen elimination and how is it solved?
the reactive intermediate that can quickly become an adduct = mutate DNA = cancer | need to attach glutathione asap
How does CYP450 make the carcinogen more water soluble?
adds an oxygen on the carcinogen = strained ester bond (unstable) = attaches beach ball on oxygen = water soluble
What is the “beach ball” that CYP450 attaches onto the reactive ester bond on the carcinogen?
glutathione (SUPER soluble)
Which DNA repair mechanism (BER or NER) removes adducts?
BER
What is the function of glutatione S-transferase (GST1)?
attaches glutathione onto the reactive oxygen
What happens if glutathione S-transferase doesn’t add glutathione the first time?
It will add it second time around
Explain the polymorphisms of CYP450.
normal = Ile/Ile = cancer risk very low | Ile/Val = cancer risk increased 74% bc GST1 may or may not be functional | Val/Val = cancer risk increased 230% GST1 doesn’t work
What is personalized medicine?
treatment tailored to specific person based on differences in gene/protein mutations compared to others of the same disease/cancer
For mutations in CYP450 gene, why may patients need personalized medicine?
if treatment doesn’t work for patient but works for other patients with same cancer = need to look at patient’s CYP450 enzymes
What are dioxins?
general category of chemicals produced by industries
What is required for the gene expression of CYP450?
receptors on our cells (Ah receptor) recognize dioxins »_space;> dioxin+receptor »_space;> induce translocation to nucleus »_space;> induces transcription of more CYP450
What are tumor initiators?
alters genetic material = starts carcinogenic process | initiated cell = hyperplasia stage
What are tumor promoters? Main function?
cause tumors from initiated cells (cells need to be initiated) and must be on the same spot as initiators | stimulate growth of initiated cells
What is TPA?
activates processes non-specifically in the cell (ie: activates kinases)
What is a complete carcinogen?
indirect or direct carcinogen causing cancer
What is an incomplete carcinogen?
carcinogen requires a promoter to cause cancer | mild damage, repairable
What is the Ames test?
used to test if chemicals are carcinogenic and determines whether it is indirect or direct carcinogen
How does the Ames test determine if the carcinogen is indirect?
will add homogenized liver (metabolic enzymes) in the plate = presence of mutagen + added enzymes = indirect carcinogen
How do stable oxidative DNA lesions occur? How is this fixable?
mutation accumulation due to DNA polymerase got confused | BER or lesion-replication polymerases
