lecture 4 biochemistry (week 2) Flashcards
what is toxicity?
toxicity isthe degree to which a chemical substance or a particular mixture of substances can damage an organism/cell
what are the intrinsic factors of toxicity?
genetic polymorphisms
sex
health of the individual
immune system
nutritional status
circadian rhythms
age
metabolic processes
species
what are the extrinsic factors of toxicity?
dose
exposure route
duration
multiple exposures
diet
co-exposure to other chemicals
voluntary behaviour
describe chemical toxicity
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)
describe biological toxicity
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
describe physical toxicity
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
describe radiation toxicity
measures harmful effects of radiation
describe behavioural toxicity
measures harmful effects of therapeutic levels of medication
what is a mutagen?
anything that causes a change in the DNA of a cell
what is a carcinogen?
a substance with causes a mutation promotion the formation of cancer
what is a teratogen?
a substance which alters the development of tissues in the foetus in the mother’s womb
what are the target organs of different toxins?
neurotoxin - neurons/brain
nephrotoxic - kidneys
hepatoxic - liver
cardiotoxic - heart
what are reactive oxygen species?
reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen
hydroperoxide (O2H)
superoxide (O2-)
hydroxyl radical (OH·)
singlet oxygen
what are sources of the reactive oxygen species?
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
what are the types of ros?
radicals - hydroxyl radical, superoxide anion, peroxyl radical, alkoxyl radical, hydroperoxyl radical
non radicals - hydrogen peroxide, hypochlorous acid, ozone, singlet oxygen, peroxy nitrile
what is a free radical?
an atom, molecule, or ion that has at least one unpaired valence electron
what are the mechanisms of ROS toxicity?
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
what are cellular antioxidant defenses?
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
describe the metabolism of xenobiotics
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
what are the phases of metabolism?
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
benzo(a)pyrene metabolism
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
describe benzo(a)pyrene diol epoxide
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
what intrinsic factors affecting detoxification enzymes?
genetic polymorphisms
sex
health of the individual
immune system
nutritional status
circadian rhythms
age
metabolic processes
species
what are the consequences of genetic variation
alters susceptibility to toxic substances
adverse drug reactions
susceptibility to cancer
