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BM321: Biomedical Biochemistry > Block B Lecture 4 - Molecular and Cellular Toxicity > Flashcards

Block B Lecture 4 - Molecular and Cellular Toxicity Flashcards

1
Q

What is toxicity?

A

Toxicity is the degree to which a chemical substance or mixture can damage an organism or cell.
(Slide 2)

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2
Q

State 5 examples of intrinsic factors which can affect toxicity?

A

Answers Include:
Genetic Polymorphisms
Gender
Health of the individual
Immune system factors
Nutritional status
Circadian rhythms
Age
Metabolic Processes
Species
(Slide 5)

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3
Q

State 5 examples of extrinsic factors which can affect toxicity / detoxification enzymes?

A

Answers Include:
Dose
Exposure Route
Duration
Number of times exposed
Diet
Co-exposure to other chemicals
Voluntary Behaviour
(Slides 5 and 25) (yes it’s the exact same list)

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4
Q

What are the 5 types of toxicity?

A

Chemical
Biological
Physical
Radiation
Behavioural
(Slide 6)

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5
Q

What does chemical toxicity measure?

A

Harmful effects of a substance to cause harmful health effects
(Slide 6)

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6
Q

State 5 examples of chemical toxins?

A

Answers Include:
Chlorine gas
Lead
Ethanol
Medications
Cyanide
Water (in extremely high doses)
Reactive oxygen species
(Slide 6)

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7
Q

What does biological toxicity measure?

A

The harmful effects of biological agents
(Slide 6)

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8
Q

What are 2 examples of biological toxins?

A

Toxins (produced by microorganisms) and venoms (produced by animals)
(Slide 6)

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9
Q

What does physical toxicity measure?

A

Harmful effects of substances, that due to their physical nature, interfere with biological processes and cause harmful health effects

(Slide 6)

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10
Q

What are 3 examples of physical toxins?

A

Asbestos fibres
Coal dust
Silicon dioxide
(Slide 6)

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11
Q

What does radiation toxicity measure?

A

The harmful effects of radiation
(Slide 6)

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12
Q

What does behavioural toxicity measure?

A

Harmful effects of therapeutic levels of medication
(Slide 6)

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13
Q

What is a mutagen?

A

Anything which causes a change in the DNA of a cell
(Slide 7)

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14
Q

What is a teratogen?

A

A substance which causes a structural or fundamental change by altering the development of tissues in the foetus in the mother’s womb - causes birth defects
(Slide 7

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15
Q

What are 4 different classification of toxins according to their target organ?

A

Neurotoxic - toxic to neurons / brain
Nephrotoxic - toxic to the kidney
Hepatotoxic - toxic to the liver
Cardiotoxic - toxic to the heart
(Slide 7)

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16
Q

What are reactive oxygen species (ROS)?

A

Highly reactive molecules containing oxygen that can damage macromolecules like DNA, lipids, and proteins

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17
Q

What are the endogenous (generated in cells) sources of reactive oxygen species (ROS)?

A

Oxidative phosphorylation (OXPHOS)
Transition metal ions
Oxidase activity
Protein folding
Thymidine and polyamine catabolism
(Slide 9)

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18
Q

What are the exogenous (generated by foreign toxins) sources of reactive oxygen species (ROS)?

A

These are as a result of the metabolism of xenobiotics (foreign toxins) or radiation therapy:
Ionisation of water following radiation treatment
Xenobiotics compromising ROS antioxidant defence systems
Xenobiotics are metabolised to a free radial or to produce / release ROS
(Slide 9)

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19
Q

What are the 2 types of ROS?

A

Radical and Non-radical
(Slide 10)

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20
Q

What is a free radical?

A

An atom, molecule or ion that has at least 1 unpair valence electron
(Slide 10)

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21
Q

What are the 2 main radical ROS?

A

Hydroxyl radical
Superoxide anion
(Slide 10)

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22
Q

Why is the hydroxyl radical ROS important?

A

As its the most reactive ROS
(Slide 10)

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23
Q

What is the main type of non-radical ROS?

A

Hydrogen peroxide
(Slide 10)

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24
Q

Why are the superoxide anion and hydrogen peroxide ROS important?

A

As they can diffuse from the site of synthesis
(Slide 10)

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25
Q

What are the 2 mechanisms which ROS can use to damage macromolecules?

A

Directly reacting with them
By damaging DNA, Lipids or Proteins
(Slide 11)

26
Q

How do ROS cause damage to DNA, lipids and proteins?

A

DNA - causes base oxidation
Lipids - causes lipid peroxidation
Proteins - causes protein carbonylation
(Slide 11)

27
Q

What is glutathione?

A

A antioxidant which reduces ROS
(Slide 13)

28
Q

What are 4 ways in which glutathione counters ROS?

A

It directly quenches some free radicals by reacting with the thiol group
It has a role in detoxification
It’s a cofactor for many antioxidant enzymes
It regenerates vitamins C and E, which are also antioxiants
(Slide 14)

29
Q

What are the 2 reasons we metabolise xenobiotics?

A

To recycle useful structures and make them more soluble to aid excretion
(Slide 16)

30
Q

Metabolism of xenobiotics is mainly carried out in the liver. What are 2 ways it does this?

A

By using the hepatic portal vein
The liver contains many of the enzymes we’ve evolved to deal with compounds found in our diets
(Slide 16)

31
Q

What are the 2 possible outcomes of metabolism of xenobiotics?

A

They either become more toxic - are activated or less toxic - detoxification
(Slide 16)

32
Q

What are the 3 phases of metabolism?

A

Phase I - Modification
Phase II - Conjugation
Phase III - Excretion
(Slide 17)

33
Q

What are 4 types of modification can occur in phase I of metabolism?

A

Oxidation
Reduction
Hydrolysis
Hydration
(Slide 17)

34
Q

What are 4 conjugations which can occur in phase II of metabolism?

A

Conjugation to glutathione
Conjugation to sulphate
Conjugation to sulphate
Acetylation
(Slide 17)

35
Q

What is often occurs in phase I of metabolism?

A

Prodrug activation
(Slide 18)

36
Q

What are 3 examples of enzymes involved in phase 1 of metabolism?

A

Cytochrome P450 monooxygenases (CYPs)
Quinone Reductase (NQO1)
Epoxide hydrolase (EH)
(Slide 18)

37
Q

State 1 enzyme involved in phase II of metabolism?

A

Glutathione S-transferases
(Slide 19)

38
Q

What is typical of products after phase II compared to before?

A

They have a higher molecular weight and tend to be less active
(Slide 19)

39
Q

What are 3 enzymes which are involved in phase 3 of metabolism?

A

Answers Include:
Xenobiotic transporters
Multiple Drug Resistance protein 1/2 (MDR1/2)
Transmembrane proteins on the plasma membrane
ATP-dependent efflux pumps
(Slide 20)

40
Q

What do the enzymes involved in phase 3 metabolism also play a role in?

A

Lipid translocation
(Slide 20)

41
Q

What is Benzo[a]pyrene?

A

It’s a polycyclic aromatic hydrocarbon which is formed by the incomplete combustion of organic matter and found in grilled meat and tobacco smoke. It is metabolised into a carcinogen
(Slide 21)

42
Q

How does Benzo[a]pyrene get converted into a carcinogen?

A

It gets activated by cytochrome P450 enzymes when it’s oxidised into Benzo[a]pyrene diol epoxide
(Slide 22)

43
Q

How does Benzo[a]pyrene diol epoxide act as a carcinogen?

A

It inserts into DNA, reacts with guanine bases, which results the DNA double helix, disrupting DNA replication and causing mutations.

It can cause G->T mutations in the p53 tumour suppressor
(Slide 23)

44
Q

What is toxicogenetics?

A

The study of how genetic differences influence an individuals susceptibility to the toxic effects of chemicals, including drugs, environmental toxins and other hazardous substances
(Slide 27)

45
Q

What are the usual 4 different genotypes in relation to metabolic polymorphisms?

A
  1. Normal metaboliser (NM)
  2. Poor metaboliser (PM)
  3. Ultra-fast metaboliser (UM)
  4. Intermediate metaboliser (IM)
    (Slide 28)
46
Q

What can genotypes other than normal metaboliser lead to?

A

Adverse drug reactions
(Slide 28)

47
Q

Why is CYP2D6 an important enzyme?

A

As hepatic CYP2D6 metabolises around 25% of prescribed drugs
(Slide 29)

48
Q

What does CYP2D6 metabolise codeine to?

A

Morphine
(Slide 29)

49
Q

How do metabolic polymorphisms effect CYP2D6’s metabolization of codeine to morphine?

A

Pain relief may be inadequate in poor metabolisers

Ultra-fast metabolisers may experience symptoms of a morphine overdose even when taking a usually therapeutic dose
(Slide 29)

50
Q

What causes the poor metaboliser polymorphism in CYP2D6?

A

A G1846A mutation located at the intron 3/exon 4 boundary, leading to aberrant mRNA splicing. This introduces extra bases and a premature stop codon, resulting in a non-functional enzyme
(Slide 30)

51
Q

What causes the ultra-fast metaboliser polymorphism in CYP2D6?

A

An increased copy number of the gene, resulting in more enzymes being active
(Slide 30)

52
Q

What region is the ultra-fast metaboliser CYP2D6 polymorphism more common in?

A

North Africa
(Slide 30)

53
Q

What are 4 consequences that DNA damage caused by mutagens can have?

A

Mutations in germ cells resulting in inherited genetic diseases
Cancer
Cell cycle arrest
Cell death
(Slide 33)

54
Q

How can ROS oxidising lipids lead to DNA damage and what are the consequences of this?

A

As lipid oxidation products can damage DNA, which results in an altered membrane dynamic, impaired membrane function and can result in membrane leakage and cell lysis - known as ferroptosis
(Slide 34)

55
Q

What 2 ways can proteins be damaged?

A

By oxidation of amino acid side chains, with sulphur-containing amino acids most at risk

Adduct formation (covalent attachment of a chemical group or molecule)
(Slide 35)

56
Q

What does the oxidation of amino acid side chains of a protein result in?

A

An altered protein conformation which may affect the function
(Slide 35)

57
Q

In what cases is protein damage especially harmful?

A

If the protein is involved in DNA repair, transcription, translation, cell cycle control or any other important biological process
(Slide 35)

58
Q

What can damage to macromolecules lead to?

A

Cell death.
(Slide 36)

59
Q

What are the characteristics of acute toxicity?

A

It occurs immediately or shortly after exposure (short latency)

Often involves a large dose over a short period (a high exposure)

Can be minor or severe

Relationship between chemical exposure and symptoms is generally obvious

Knowledge often based on human exposure
(Slide 40)

60
Q

What are the characteristics of chronic toxicity?

A

It occurs over time or long after exposure (long latency)

Often involves small and repetitive doses (low exposure) over a long period

Often involves inflammation and scarring of organs

Chronic effects are usually unknown for many chemicals

It may be difficult to establish the relationship between chemical exposure and illness due to a long time delay or latency period

Knowledge often based on animal studies
(Slide 40)

BM321: Biomedical Biochemistry (10 decks)

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