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bm321: biomedical biochemistry > lecture 4 biochemistry (week 2) > Flashcards

lecture 4 biochemistry (week 2) Flashcards

1
Q

what is toxicity?

A

toxicity isthe degree to which a chemical substance or a particular mixture of substances can damage an organism/cell

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2
Q

what are the intrinsic factors of toxicity?

A

genetic polymorphisms

sex

health of the individual

immune system
nutritional status

circadian rhythms

age

metabolic processes

species

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3
Q

what are the extrinsic factors of toxicity?

A

dose

exposure route

duration

multiple exposures

diet

co-exposure to other chemicals

voluntary behaviour

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4
Q

describe chemical toxicity

A

measures harmful effects of a substance to cause harmful health effects, e.g.:

chlorine gas

lead

ethanol

medications

cyanide

water(!) if taken at extremely high doses

reactive oxygen species (ROS)

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5
Q

describe biological toxicity

A

measures harmful effects of biological agents, e.g.:

non-living biological toxicants

toxins – those produced by microorganisms

venoms – those produced by an animal

disease-causing microorganisms and parasites although toxic they are called pathogens

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6
Q

describe physical toxicity

A

measures harmful effects of substances, that due to their physical nature, interfere with biological processes and cause harmful health effects, e.g.:

asbestos fibres

coal dust

silicon dioxide

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7
Q

describe radiation toxicity

A

measures harmful effects of radiation

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8
Q

describe behavioural toxicity

A

measures harmful effects of therapeutic levels of medication

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9
Q

what is a mutagen?

A

anything that causes a change in the DNA of a cell

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10
Q

what is a carcinogen?

A

a substance with causes a mutation promotion the formation of cancer

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11
Q

what is a teratogen?

A

a substance which alters the development of tissues in the foetus in the mother’s womb

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12
Q

what are the target organs of different toxins?

A

neurotoxin - neurons/brain

nephrotoxic - kidneys

hepatoxic - liver

cardiotoxic - heart

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13
Q

what are reactive oxygen species?

A

reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen

hydroperoxide (O2H)

superoxide (O2-)

hydroxyl radical (OH·)

singlet oxygen

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14
Q

what are sources of the reactive oxygen species?

A

endogenous (generated by cells) - transition metal ions, oxidase activity, protein folding, thymidine and polyamine catabolism, oxidative phosphorylation

exogenous (generated by foreign toxins; xenobiotics) - ionisation of water following radiation treatment, xenobiotics compromising ROS antioxidant defence systems, xenobiotics are metabolised to a free radical, xenobiotics are metabolised to produce/release ROS

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15
Q

what are the types of ros?

A

radicals - hydroxyl radical, superoxide anion, peroxyl radical, alkoxyl radical, hydroperoxyl radical

non radicals - hydrogen peroxide, hypochlorous acid, ozone, singlet oxygen, peroxy nitrile

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16
Q

what is a free radical?

A

an atom, molecule, or ion that has at least one unpaired valence electron

17
Q

what are the mechanisms of ROS toxicity?

A

direct damage to macromolecules by reacting with them

ROS will cause reversible and irreversible damage to macromolecules, including:

DNA by causing base oxidation

lipids by causing lipid peroxidation

proteins by causing protein carbonylation

18
Q

what are cellular antioxidant defenses?

A

they protect cells by reducing ros

glutathione - antioxidant, tripeptide –> glutamate, cysteine and glycine

unusual gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine

very high expression in cells (up to 5 mM)

in healthy cells 90% of the glutathione pool will be in the reduced form

directly quenches some free radicals by reacting with the thiol group

role in detoxification

cofactor for many antioxidant enzymes

regenerates vitamin C and E, which are antioxidants

19
Q

describe the metabolism of xenobiotics

A

two purposes:

recycle useful structures
make more soluble to aid excretion

mainly carried out in the liver

hepatic portal vein

many of the enzymes evolved to deal with compounds found in our diets (and normal biosynthetic rolls-sterols)

two possible outcomes of metabolism

compound becomes more toxic - activation

compound becomes less toxic - detoxification

20
Q

what are the phases of metabolism?

A

phase 1 (modification)

oxidation, reduction, hydrolysis, hydration

oxidation - cytochrome p450 monooxygenases (CYPs)

reduction - quinone reductase (NQ01)

hydration - epoxide hydrolase (EH)

phase 2 (conjugation)

conjugation to glutathione, conjugation to sulphate, conjugation to glucuronide, acetylation

conjugation to glutathione - glutathione S transferases

conjugation to charged species

products have a higher molecular weight and tend to be less active

polar/charged product cannot diffuse across the cell membrane

necessitates active transporters

phase 3 (excretion)

xenobiotic transporters

multiple Drug Resistance protein 1/2 (MDR1/2)

transmembrane proteins on the plasma membrane

ATP-dependent efflux pumps

physiological role in lipid translocation

upregulated in many cancers

21
Q

benzo(a)pyrene metabolism

A

polycyclic aromatic hydrocarbon

formed by the incomplete combustion of organic matter

found in grilled meat and tobacco smoke

metabolised into a carcinogen - benzo(a)pyrene diol epoxide

22
Q

describe benzo(a)pyrene diol epoxide

A

active carcinogen

intercalates into DNA

reacts with guanine bases

this distorts DNA double helix

disrupts DNA replication and causes mutations

causes G→T mutations in tumour suppressor p53

23
Q

what intrinsic factors affecting detoxification enzymes?

A

genetic polymorphisms

sex

health of the individual

immune system

nutritional status

circadian rhythms

age

metabolic processes

species

24
Q

what are the consequences of genetic variation

A

alters susceptibility to toxic substances

adverse drug reactions

susceptibility to cancer

25
Q

what is toxicogenetics?

A

the study of how genetic differences influence an individual’s susceptibility to the toxic effects of chemicals, including drugs, environmental toxins, and other hazardous substances

26
Q

what are the 4 main genotypes in metabolim of xenobiotics?

A

normal metaboliser = wt

poor metaboliser PM = lower mutation, lower mutation

ultra-fast metaboliser UM = higher mutation, higher mutation

intermediate metaboliser IM = lower mutation, wt

2-4 can all lead to adverse drug reactions

27
Q

describe CYP2D6 and codeine

A

hepatic CYP2D6 metabolises ~25% of prescribed drugs

metabolises codeine to morphine

CYP2D6 is highly polymorphic- over 100 alleles have been described

pain relief may be inadequate in poor metabolisers

others are ultra-fast metabolisers and have a rapid increase in morphine

may experience symptoms of morphine overdose as a result of a usually therapeutic dose

28
Q

poor metabolisers and codeine

A

0.4-6.5% population
CYP2D6*4 (G1846A)
located at intron 3/ exon 4 boundary.

causes a shift of the consensus acceptor splice site = spliced

mRNA has extra bases and a premature stop codon

CYP2D6*5 (gene deletion)

29
Q

ultra-fast metabolisers

A

1-2% individuals, up to 10% in North African populations.

associated with increased copy number.

30
Q

describe lipid damge

A

especially targeted by lipophilic compounds

ROS causes lipid oxidation

lipid oxidation products can damage DNA

results in altered membrane dynamics

impaired membrane function

membrane leakage and cell lysis in a process called ferroptosis

31
Q

describe protein damage

A

oxidation of amino acid side chains

sulphur-containing amino acids are at risk
alter protein
conformation which may affect the function

also protein adduct formation

particularly bad news if the protein is involved in DNA repair, transcription, translation, cell cycle control etc.

bm321: biomedical biochemistry (9 decks)

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