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PED3011 Toxicology > Non-genotoxic Carcinogens > Flashcards

Non-genotoxic Carcinogens Flashcards

1
Q

What is the difference between and genotoxic and non-genotoxic carcinogen

A

Gentoxic: mutagenic = cancer
Non-genotoxic: non-mutagenic = cancer

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2
Q

What kind of result would a non-genotoxic carcinogen show in an Ames test

A

Negative

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3
Q

What is the most effective non-genotoxic carcinogen with implications for human health

A

Fibrate drugs

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4
Q

Describe the Ames test

A

Use of bacteria that are unable to grow without the presence of a certain compound
E.g histidine auxotrophic mutants of salmonella = can’t synthesise histidine

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5
Q

What would positive Ames test look like

A

Increased revertants near test chemical

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6
Q

What can be added to the aims test to improve the accuracy

A

Rat liver microsomes (S9)

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7
Q

Why does adding S9 improve Ames test accuracy

A

Compounds are often genotoxic after metabolism
S9 metabolises compounds to see if they are truly genotoxic

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8
Q

What is atherosclerosis

A

Fatty plaques in blood vessels
Can cause vessel occlusion = heart attack

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9
Q

What do Fibrate drugs treat

A

Atherosclerosis and high blood lipid levels
Rarely used

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10
Q

How do lipids enter the blood after digestion

A

Lipids -> GI Tract -> Blood -> hepatic portal vein -> liver

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11
Q

How does the lipid release lipids

A

Very low density lipoproteins (vLDL)

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12
Q

How can cholesterol be transported

A

As cholesterol-esters

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13
Q

What happens to vLDL as it moves around the body

A

vLDL -> LDL -> HDL
Becomes less dense due to losing lipids

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14
Q

What is the role of adipose

A

Take up triglycerides for emergency storage in times of starvation
Will break down stores to fuel other tissues e.g muscles

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15
Q

What does high HDL levels in the blood suggest

A

The body is capable of dealing with lipids and can remove lipids from circulation

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16
Q

What is the typical molecular structure of fibrates

A

Carboxylic acids
Have ester bond that can produce carboxylic acids

Mimic fatty acid structure

17
Q

How do Fibrate drugs work

A

Act by decreasing serum triglycerides
Variable effects on LDL-cholesterol
Reduce production of cholesterol

18
Q

What is the effect of fibrates in mice

A

100% liver tumour incidence by year 1
Primary liver cancer is rare especially in rodents

19
Q

Describe hypertrophy as a result of fibrates in mice

A

Increase in cell size
Most likely an adaptive response and not adverse effect

20
Q

How is hepatocyte proliferation affected by fibrates in mice

A

Significant increase in proliferation

21
Q

How can hepatocyte proliferation be analysed

A

Inject mice 1 hour before euthanasia with BrdU (dT analogue)
Cells will incorporate BrdU
Those that are proliferating will have higher DNA conc = more BrdU incorpated

22
Q

How do fibrates effect peroxisomes proliferation

A

Significant increase

23
Q

What is the role of peroxisomes

A

Fatty acid metabolism

24
Q

Describe fatty acid metabolism (beta-oxidation)

A

Oxidise and remove 2 carbon units from fatty acid
Shorten the chain by 2 units each time

25
Q

What is the difference between fatty acid metabolism in the mitochondria and peroxisomes

A

Mitochondria produce Ac-CoA, 2xH2O and NADH
Peroxisomes produce Ac-CoA, H20, H2O2 and NADH

26
Q

What is the mechanism that peroxisomes use to deal with the H2O2 produced

A

Low [Fe2+] and high levels of catalase (bind H2O2)

27
Q

Why is it dangerous to have high levels of H2O2 in cells

A

Fenton reaction produces hydroxyl radical from Fe2+ which reacts with everything instantly

28
Q

How is free Fe2+ kept low in cells

A

Bound to ferritin

29
Q

What CYP to fibrates induce

A

CYP4A

30
Q

What is the function of CYP4A

A

To oxidise fatty acids

31
Q

What is the proposed mechanism of action of fibrates

A

Induce CYP4A = monoxygenation of fatty acids to -COOH
-> beta-oxidation can occur at both ends = double the rate of beta-oxidation
= increase breakdown of fatty acids

32
Q

What nuclear receptor do fibrate drugs bind to

A

Peroxisome proliferator activated receptor -alpha
PPARa

33
Q

What happens when a ligand binds to the PPARa

A

Receptor heterodimerises with another nuclear receptor and translocates to the nucleus
Binds to response elements within the genes it regulates

34
Q

Where is PPARa mainly expressed

A

Liver and kidney

35
Q

What does PPARa regulate

A

Expression of genes associated with peroxisome proliferation
B-oxidation of fatty acids
Cholesterol reduction e.g HDL synthesis

36
Q

What happens is the PPARa is knocked out in mice

A

Removes all effects
Suggest its responsible for directing biological responses in response to fibrates

37
Q

What evidence is there that Fibrate drugs will not cause liver cancer in humans

A

Only lipid lowering effect observed in humans
No evidence of liver growth
PPARa expression is only 5-10% of rodent liver

38
Q

What is the suggested mechanism of non-genotoxic carcinogens in rodents

A

The altered balance between proliferation and apoptosis

PED3011 Toxicology (11 decks)

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