Into lectures Flashcards
What are toxicants?
compounds that interact at a molecular or tissue level to alter homeostasis of the organism
What are some toxicants?
Xenobiotics (foreign chemicals) - industrial/agricultural chemicals, environmental pollutants, food contaminants/additives, drugs
‘natural’ toxins - mycotoxins, phytotoxins, endotoxins
How are we exposed to toxicants?
- Enivronmental exposure (air, water, food contamination)
- Occupational exposure
- Intentional exposure
By what routes can toxicants enter the body and what effects do these have?
- Dermal (skin)
- Inhalation (lungs)
- Ingestion (GI)
Influences target organ (primary target organ often lungs or skin)
If ingested may cause GI damage or liver toxicity
Toxicants get concentrated in the kidney tubule during excertion, so toxicants eliminated via the kidney may cause toxicity
What physiochemical properties effect passage through a cellular membrane?
- chemical structure (relative lipid solubility, degree of ionisation)
- selectivity for transporter proteins
What is the difference between direct and indirectly acting toxicants?
Indirectly acting toxicants require enzymatic conversion into a reactive chemical within a cell
What is an example of a directly acting toxicant?
Hydrogen Cyanide (HCN)
- is a weak acid
- readily forms cyanide anion at biological pH
- highly reactive CN- group
- especially reactive with metals such as iron
- inhibits cytochrome c oxidase by binding the iron group, therefore inhibiting cellular respiration
What are potential macromolecular targets in a cell?
lipids
proteins
nucleic acids
can be widespread r specific targeted effects
Specific interactions include the ability of the toxicant to…
- prevent or compete with normal ligand binding, inhibiting function
- mimic a natural ligand and increase response
- disrupt the function of enzymes, binding/transport proteins and receptors/ion channels (aberrant function)
Nonspecific interactions of toxicants with critical biomolecules are due to…
- the chemical reactivity of the compound
- the proximity to the target (dependent on conc)
What is observed if damage is too large and escapes repair?
- irreversible injury, oncotic cell death - this is the critical end point of injury
- observed as necrosis
What are the 5 events that are associated with toxic injury to cellular biomolecules?
- Formation of ROS
- Degradation of damaged cellular proteins
- ATP depletion
- Loss of selective membrane permeability
- Loss of calcium homeostasis
Event 1: Formation of ROS
- results in oxidative stress in a cell
- ROS and RCS can also be generated as part of infection, allergy, diet, and physical damage
- Formed during the generation of ATP in mitochondria (4 electron reduction of oxygen to water)
- Can also be formed as by-products of cyp450 and hemoglobin
What are ROS?
- short lived free radical intermediates
- O2- superoxide ion (1 electron reduction)
- H2O2 (2 electron reduction)
- hydroxyl radical (3 electron reduction)
Differ in reactivity and stablity (hydroxyl most reactive, superoxide can diffuse farthest)
Superoxide Dismutase….
converts superoxide to hydrogen peroxide
Fe in metalloproteins can catalyse….
superoxide to hydroxyl radical
myeloperoxidase….
- used by granulocytes
- hydrogen peroxide + chloride ion => HOCl + hydroxyl ion
What produce RNS?
- endothelial cells
- macrophages during inflammation
NO can interact with ROS to form RNS
peroxynitrate can cause oxidative cellular damage by nitrosylation
What are some RCS?
Xenobiotics can be
Free radicals
Unstable electrophilic species
What methods do we have to protect against reactive species?
- Antioxidants e.g. alpha-tocopherol and glutathione
- enzymes which detoxify reactive species e.g. SOD, glutathione peroxidase, glutathione synthase, catalase
Depleting either of these can result in cell injury, interfering with cellular functioning
What is glutathione?
A tripeptide containing cysteine
Found in cytosol of most cells at milimolar conc
Thiol group of cysteine acts as nucleophile (reacts w/ RCS,ROS,RNS, decreasing toxicity)
The reaction with reactive species can be direst or enzymatic (GST)
Effect of ROS on lipids
- membrane lipids undergo peroxidation (hydroxyl radical reacts to form lipid hydroperoxide radical)
- Highly reactive LOO. radical can react further with lipids - self-perpetuating reaction
- increased permeability of membrane
- mitochondira particularly susceptible
Effect of ROS on DNA
- Mutagenesis - specific damage, heritable (e.g. nitrogen mustard derivates)
- Teratogenesis - can damage embryonic/fetal development (e.g. radiation, thalidomide, alcohol)
- Carcinogenesis - results in uncontrolled proliferation of tissue (polycyclic aromatic hydrocarbons, aflatoxin)
can damage DNA in both replicating and non-replicating cells
Effect of ROS on proteins
- proteins containing thiol groups are susceptible to oxidation (especially in cysteine residues)
- can alter function of ion pumps, resulting in highly perturbed cellular ion homeostasis (cell oedema and death. e.g. Ca and Na/K ATPases)
- subtle damage such as oxidation of regulatory proteins altering pathways, or changing functions of a cellular process
oxidised cell proteins can act as redox sensors - NFkB and AP-1 are sensitive to oxidative stress. Thiol mod. Can alter gene expression
What are some examples of response elements?
- Antioxidant response element (ARE)
- Electrophilic response element (EpRE)
- tetradecanylphorbyl acetate response element (TRE)
they are located in the promoter regions of specific genes.
