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
