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PED3011 Toxicology > Inter-species + Inter-individual Differences > Flashcards

Inter-species + Inter-individual Differences Flashcards

1
Q

What is included in pre-clinical toxicity screening

A

Mutagenicity
Carcinogenicity
Reproductive toxicity
Acute toxicity
Subchronic toxicity
Chronic toxicity

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2
Q

Describe the use of rodents in toxicology studies

A

Usually rats as they’re standardised
Mice can be genetically manipulated and organ systems are more reproducible
-> guinea pigs better

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3
Q

Describe the use of non-rodents in toxicology studies

A

Not commonly used anymore
Dogs usually used to test cardiovascular effects
Mini-pigs have a similar cardiovascular system to humans
Rabbits have a similar reproductive cycle so are used in reproductive toxicity

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4
Q

When would primates be used in toxicity studies

A

Used to study CNS effects due to their similar CNS
Antibody therapy as their immune system is most similar to humans

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5
Q

How could the toxicological effect of long term administration be monitored

A

6-12 month toxicological studies in rodents and non-rodents

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6
Q

How can a chemical be tested for it carcinogenicity

A

Lifetime exposure in rats and/or mice

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7
Q

How can the complete metabolic fate of a chemical be monitored

A

Characterisation of the complete metabolic profile often using radiolabelling
Shows if the active metabolites contribute to efficacy or toxicity

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8
Q

How can potential chemical interactions be excluded based on previous knowledge

A

Identification of metabolising enzymes responsible for the new chemical metabolism
In vitro chemical interaction studies using humane enzymes

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9
Q

Descirbe the ideal animal model

A

Replicates the human metabolism of the chemical
Share the same molecular pathways and enzymes
Should be a good model for a given human disease

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10
Q

What are the factors affect drug metabolism in lab animals

A

Lab animals are in a controlled environment and lack genetic diversity
Limited effects of sex differences
= controlled and stable metabolism

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11
Q

What are the factors affect drug metabolism in the human population

A

High levels of genetic diversity
Environmental and lifestyle pressures
Impact of sexdifferences
= No control and variable metabolism

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12
Q

What variation in metabolism is there between species

A

Difference in proportion, specificity and distribution of phase I and phase II enzymes
Different in mechanisms regulating phase I and phase II enzyme expression
Difference in responses to DNA damage between animals and humans

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13
Q

What variation in metabolism is there between humans

A

Population diversity: SNP’s, age, body fat, gender and health status
Extreme conditions
Exposure

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14
Q

Describe the difference in CYP450 distribution between human and rat livers

A

Might see CYPS in rats that we don’t see in human e.g CYP2C11
Different levels of CYPS: higher levels of CYP1A2 and 2E1 in humans that rats
= might not see some toxic effects in rats but in humans

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15
Q

What are the advantages and disadvantages of testing toxicity in lab animals

A

Adv: helps deduces the mechanism of toxicity
Dis: limited experimental approach that implies they share the same metabolic pathway

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16
Q

What chemical is a good example of the difference in drug metabolism in humans vs rats

A

Nicotine
In humans metabolised by CYP2A6 which is highly expressed and a SNP causes nicotine dependence
But in rats nicotine is metabolised by CYP2B

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17
Q

How does phase II metabolism vary between species

A

Promotion of phenol conjugated to glucuronides and sulfates
Can lead to significant variation in metabolism between species

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18
Q

How do gender differences effect CYP450 levels in humans and rodents

A

Humans: no major differences
Rodents: CYP3A, 2A, 2B and 2C higher in males than females

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19
Q

How do inter-species differences effect hydrolysis of esters in humans vs rodents

A

Higher level of cholinesterases in humans than rodents
Higher level of carboxylesterases in rodents than in humans

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20
Q

How does age affect metabolism in humans

A

Long life span
Children: many changes to P450s in the first 4 years of life
Adults: specific activity does not decrease with age
Elderly: reduced liver size and liver blood flow = reduced clearance by metabolism

21
Q

How does age effect metabolism in rodents

A

Limitations for long-term exposure
Have short life span of approx 2 years
Have ‘mature’ P450s at 6 weeks = difficult to study toxicology in children

22
Q

What is the difference in biliary excretion between species

A

Cut off point in terms of MC for biliary vs renal excretion
Might be due to differences in specificity for ABCC2 transporter

23
Q

Describe how genetic differences between DA rats have an effect on their ability to reduce high blood pressure

A

Female DA lacks CYP2D1 = can’t hydroxylate debrisoquine
Male DA express a male specific CYP2D isoform = can hyroxylate debrisoquine

24
Q

What is a good model to study debrisoquine toxicity for CYP2D6 ‘poor metabolisers’

A

Female DA

25
Q

What is a good model for paracetamol induced hepatoxicty in individuals with a SNP in UGT1A

A

Gunn rat
Unable to synthesise certain phenol glucuronides

26
Q

What are some sex and tissue differences related to carcinogens

A

Genotoxic carcinogens: can cause can in any tissue, multispecies
Non-genotoxic carcinogens: maybe tissue specific, show sex differences

27
Q

What is the proposed mechanism of carcinogenicity of unleaded petrol in male rats

A

Normal renal cells + TMP -> renal uptake of a2-microglobulin-TMP complex
= lysosomal overload -> cell death -> regenerative hyperplasia
= renal tumours

28
Q

Why is there no carcinogenicity of unleaded petrol in female rats

A

Synthesis of a2-microglobulin is under hormonal control
= make 1% compared to makes
= no complex -> no uptake -> no hyperplasia -> no tumours

29
Q

Describe the PPAR-a

A

Nuclear receptor and txn factor
Indices txn of CYP3A4 and CYP4A
Agonist used as hypolipidaemic drugs

30
Q

How do mice and rats respond to PPARa agonists

A

Highly responsive
Liver tumours

31
Q

How do guinea pigs respond to PPARa agonists

A

No peroxisome proliferation
Hypolipidaemia
No evidence of liver tumours

32
Q

How do dogs and marmosets respond to PPARa agonists

A

No response
No evidence of liver tumours

33
Q

How do humans respond to PPARa agonists

A

Believed to be unresponsive
Evidence of hypolipidaemia

34
Q

Why is there no hepatocarcinogenesis in human compared to rats after being administered PPARa agonists

A

Human: insufficient levels of PPARa to induce cell proliferation
Rat/mouse: higher PPARa levels = cell proliferation

35
Q

What is tamoxifen

A

Non-steroidal anti-oestrogen if treatment of breast cnacer
Blocks oestrogen binding to receptor
Metabolised to compounds that bind to oestrogen receptor but do not activate it

36
Q

What species specific genotoxic effects does tamoxifen have

A

Male rats: hepatocellular carcinomas
Female rats: hepatocellular and endometrial carcinomas
Mice: rare hepatocellular carcinomas
Human: no hepatocellular carcinomas

37
Q

Describe how tamoxifen metabolism differs in rats vs humans

A

Tamoxifen -> 4OH-tamoxifen via CYP3A4
Humans: 4OH-tamoxifen glucuronidated and detoxified
Rats: 4OH-tamoxifen is sulfated which is genotoxic

38
Q

What is the active form of tamoxifen

A

Endoxifen
4OH-tamoxifen -> endoxifen via CYP2D6

39
Q

How can SNPs affect response to medication

A

Results in alteration of amino acid sequence of protein
= could result in phenotypic differences between subjects

40
Q

Describe PON1

A

Synthesised in liver, secreted in plasma where it associates w HDL
Detoxifies OPs

41
Q

Describe the SNP Q192R in PON1

A

Induces AA change in position 192 = change in substrate specificity and affects protein levels
Q isoform = rapid metabolisers of diazinon and nerve agents
R isoform= rapid metabolisers of paraoxon

42
Q

What SNP in PON1 affects protein levels but not activity

A

L55M
Leucine -> methionine at position 55

43
Q

How does older age affect distribution of drugs

A

Altered blood flow and decreased clearance
Changing in volume of distribution = hydrophobic chemicals stored in fat tissue

44
Q

How does older age affect the absorption of drugs

A

Decreased inaction capacity
Increased dermal absorption due to thinner skin
Decreased gut absorption due to impaired wall function

45
Q

Describe the effect of older age on metabolism

A

Decrease in expression of metabolic enzymes and plasma protein transporting drugs

46
Q

Describe drug absorption in neonates

A

Increased dermal absorption
Decreased gut absorption

47
Q

Describe the distribution of drugs in neonates

A

Increased susceptibility due to different fat/water ratio

48
Q

Describe the metabolism of drugs in neonates

A

Some metabolic enzymes are underdeveloped e.g P450s and UDPs

49
Q

Describe excretion of drugs in neonates

A

Immature renal function = reduced excretion

PED3011 Toxicology (11 decks)

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