Lecture 1 Flashcards
What are the 4 principle steps of toxicity?
Delivery, interaction with target molecule or biological environment, induce cellular dysfunction/injury, inappropriate repair/adaptation
what is toxicokinetics
What the body does to the toxicant (how it reaches the target)
What is type 2a toxicity?
specific interaction (ie. tetradotoxin) inhibits Na+ channels and leads to paralysis
What is type 2b toxicity?
Non specific interaction (ie. dinitrophenol)
uncouples the oxidative phosphorylation chain by reducing the proton gradient across the inner mitochondrial membrane
What are the most common routes of toxicant delivery?
GI tract, lungs and skin
Is metabolism a positive or negative effect?
Depends on the substance. It could detoxify a toxicant or create a toxic metabolite from a otherwise non toxic substance.
What are enterocytes?
Epithelial cells in the intestine
How do enterocytes transport drugs?
Through drug trasporters on both the lumen and the basolateral (blood) side.
What are hepatocytes? What are their key features?
The parenchymal cells of the liver. They uptake toxicants through the blood and excrete into the bile or liver veins. They also metabolize drugs.
What is the BBB? what can be transported?
a function of the endothelial cells in the brain. Only small water soluble or lipophilic substances can enter by diffusion. other molecules have to be transported.
Can lipophilic compounds be renally excreted? Does the kidney excrete large compounds? What can reabsorption do?
No, they prefer small molecules (<330da) and reaborption could retain toxicants.
What is phase 1 metbolism?
Usually oxidation (to create electrophiles) or reduction (to create nucleophiles)
What is phase 2 metabolism?
Usually conjugation reactions. Electrophiles undergo glutathione conjugation and nucleophiles under either sulfation, acetylation or glucuronidation.
What are the 3 principle methods of free radical formation?
Acceptance of electrons by CYP reductase, removal of electrons by peroxidases and homolytic fission of a covalent bond (ie. fenton reaction).
What are the 4 types of binding with a target?
Reversible (non-covalent, ie warfarin), Irreversible (covalent), Hydrogen abstraction and electron transfer
What are the 4 types of effects with a target?
Activation (morphine activating opiod receptor), inactivation (S-S bonds inactive proteins), destruction (lipid peroxidation) and neoantigen formation (haptens and prohaptens).
What is repair and adaptation in terms of toxicology?
Repair refers to fixing the damage done to the cell and adaptation is the cell learning to cope better to toxicants
How are oxidised proteins (prot-S-S-prot etc.) repaired?
Thioredoxin pathway can reduce these bonds
How are denatured proteins repaired?
Disaggregation possible by heat-shock proteins and these proteins can also assist with ubiquitination and proteasomal degradation
How are lipids repaired?
When fatty acid radicals are produced they are converted to peroxides (dependent on tocopherol, ascorbate and NADPH) which is then excised and reduced by glutathione peroxidase
How is DNA repaired?
DNA is initially protected by histones along with repair mechanisms. They can be repaired directly (no base excision), by excision repaire and also homo/non homologous recombination
What is TP53 and what is its role in DNA regulation?
TP53 is a transcription factor that stimulates important proteins (ie. p21) for the cell cycle. It can also stop the cell cycle to allow time for DNA repair
What is the basics of cellular repair processes?
Apoptosis, necrosis, mitophagy (elimination of mitochondria).
When is cell deletion used?
During the tissue repair process and its used by cells with the ability to multiply. Deletion achieved either by apoptosis or necrosis
What process usually follows cell deletion and how does it work?
Cell multiplication occurs after cell injury and usually after cell deletion. It is controlled by cyclins and use to reach regular cell number again
What are common mediators of the tissue repair cycle?
Macrophages degrade dying cells and in the process secrete TNF-alpha and Growth factors (ie. TGF-beta) which promote cell proliferation
What are side effects of tissue repair?
Inflammation when necrosis dominates (TNF-alpha and IL-1) and production of ROS and RNS (NADPH oxidase in macrophages)
What are mechanisms of adaptation?
Decreased delivery to the target, increased compensation and or defense mechanisms and increased repair capacity
What is an example of antioxidative defense?
Nrf2 is normally attached to Keap1 and degraded. When cells undergo oxidative stress Keap1 is phosphorylated and Nrf2 can enter the nucleus and active important antioxidative genes.
What are examples of increased repair responses?
Electrophile response (thioredoxin system), Heat-shock response (HSF1 transcription factor release into cytosol), ER stress response, DNA damage response and proliferative response
What happens when repair/adaptation fail?
Consequences include fibrosis or carcinogenesis
