4 - Chemical Carcinogenesis

Question 1

What are direct carcinogens?

Answer 1

able to directly act on DNA alone right away | ie: adducts

Question 2

What are indirect carcinogens?

Answer 2

carcinogen needs to be enzymatically broken down = intermediates/byproducts directly act on DNA | carcinogen itself doesn’t directly act on DNA, its the byproducts

Question 3

How can compounds produced from industrial plants cause us cancer?

Answer 3

dumping those hydrophobic compounds in water &raquo_space;> compounds get stuck on fish gills &raquo_space;> we eat the fish = we now have the hydrophobic compounds

Question 4

What are DNA intercalating agents?

Answer 4

carcinogens that intercalate between base pairs and disrupt DNA synthesis | ie: acridine orange and PCBs

Question 5

What is synergy? (chemical interaction)

Answer 5

the effect of 2 or more chemicals taken together = greater than the sum of their separate effects

Question 6

What is additive? (chemical interaction)

Answer 6

chemical A effect + chemical B effect = additive effect of chemicals A and B

Question 7

Are most carcinogens lipophilic? What is lipophilic and what do these carcinogens require to be effective?

Answer 7

most carcinogens = lipophilic = hydrophobic = need to be metabolized to take effect

Question 8

What are the 4 pathways our bodies eliminate toxin?

Answer 8

renal | hepatic | intestinal | local neutralization

Question 9

What happens if the carcinogen is not eliminated from the body?

Answer 9

accumulated in the tissues

Question 10

What is renal clearance?

Answer 10

carcinogen/toxin clearance via kidneys

Question 11

What is the role of the kidneys in toxin elimination?

Answer 11

filters out blood &raquo_space;> gets rid of hydrophilic chemicals (water soluble) &raquo_space;> excreted as pee

Question 12

What is hepatic clearance?

Answer 12

carcinogen/toxin clearance via liver

Question 13

What is the role of the liver in toxin elimination?

Answer 13

filters out blood &raquo_space;> gets rid of lipophilic chemicals (water-insoluble/fat-soluble) &raquo_space;> excreted as poop

Question 14

What is the goal of carcinogen elimination?

Answer 14

take carcinogen through hepatic clearance or make them water soluble for renal clearance

Question 15

What are the phases of carcinogen elimination?

Answer 15

Phase I and Phase II

Question 16

What is Phase I of carcinogen elimination? What is the enzyme(s) involved?

Answer 16

activates carcinogen | cytochrome P450 (CYP450)

Question 17

What is the function of CYP450?

Answer 17

helps detoxify carcinogen by trying to make it water soluble

Question 18

What is Phase II of carcinogen elimination? What is the enzyme involved?

Answer 18

detoxify carcinogen via conjugation | glutathione S-transferase (GST1) (and others too)

Question 19

What activates CYP450?

Answer 19

reductase

Question 20

What is the dangerous part of Phase I in carcinogen elimination and how is it solved?

Answer 20

the reactive intermediate that can quickly become an adduct = mutate DNA = cancer | need to attach glutathione asap

Question 21

How does CYP450 make the carcinogen more water soluble?

Answer 21

adds an oxygen on the carcinogen = strained ester bond (unstable) = attaches beach ball on oxygen = water soluble

Question 22

What is the “beach ball” that CYP450 attaches onto the reactive ester bond on the carcinogen?

Answer 22

glutathione (SUPER soluble)

Question 23

Which DNA repair mechanism (BER or NER) removes adducts?

Answer 23

BER

Question 24

What is the function of glutatione S-transferase (GST1)?

Answer 24

attaches glutathione onto the reactive oxygen

Question 25

What happens if glutathione S-transferase doesn't add glutathione the first time?

Answer 25

It will add it second time around

Question 26

Explain the polymorphisms of CYP450.

Answer 26

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

Question 27

What is personalized medicine?

Answer 27

treatment tailored to specific person based on differences in gene/protein mutations compared to others of the same disease/cancer

Question 28

For mutations in CYP450 gene, why may patients need personalized medicine?

Answer 28

if treatment doesn't work for patient but works for other patients with same cancer = need to look at patient's CYP450 enzymes

Question 29

What are dioxins?

Answer 29

general category of chemicals produced by industries

Question 30

What is required for the gene expression of CYP450?

Answer 30

receptors on our cells (Ah receptor) recognize dioxins >>> dioxin+receptor >>> induce translocation to nucleus >>> induces transcription of more CYP450

Question 31

What are tumor initiators?

Answer 31

alters genetic material = starts carcinogenic process | initiated cell = hyperplasia stage

Question 32

What are tumor promoters? Main function?

Answer 32

cause tumors from initiated cells (cells need to be initiated) and must be on the same spot as initiators | stimulate growth of initiated cells

Question 33

What is TPA?

Answer 33

activates processes non-specifically in the cell (ie: activates kinases)

Question 34

What is a complete carcinogen?

Answer 34

indirect or direct carcinogen causing cancer

Question 35

What is an incomplete carcinogen?

Answer 35

carcinogen requires a promoter to cause cancer | mild damage, repairable

Question 36

What is the Ames test?

Answer 36

used to test if chemicals are carcinogenic and determines whether it is indirect or direct carcinogen

Question 37

How does the Ames test determine if the carcinogen is indirect?

Answer 37

will add homogenized liver (metabolic enzymes) in the plate = presence of mutagen + added enzymes = indirect carcinogen

Question 38

How do stable oxidative DNA lesions occur? How is this fixable?

Answer 38

mutation accumulation due to DNA polymerase got confused | BER or lesion-replication polymerases