Mechanisms of Toxicity Flashcards
Identify the key steps in the development of a toxicosis.
- step 1
- delivery from site of exposure to target organs
- intensity of toxic effect depends on concentration and persistence of the ultimate toxicant at site of action
- step 2
- interaction with target or alteration of microenvironment
- step 3
- cellular dysfunction and injury
- step 4
- dysrepair or repair
Define ‘ultimate toxicant’.
- the chemical species that reacts with endogenous target molecules or alters the biological microenvironment
In what way(s) does first-pass elimination affect the toxic response?
- it is the loss of a toxicant during transfer from the site of exposure to systemic circulation
- metabolized by liver or GI before reaching circulation
- this reduces toxicity of toxicants delivered to target sites via circulation
- increases risk of toxicity to liver and GI
- toxic effects are prolonged and effective dose reduced
- specifically with enterohepatic circulation
- AKA presystemic elimination
Explain how porosity of capillary endothelium, P-glycoproteins, and binding to plasma proteins affect distribution of toxicants.
- porosity allows distribution
- P-glycoproteins limit distribution
- plasma protein binding limits distribution
- only free toxin can get out of circulation
Provide three ways by which toxicants undergo activation. Which one is considered most important?
- acquiring features that harm the biological microenvironment
- acquiring greater reactivity
-
indiscriminate reactivity
- electrophiles, neutrophiles, free radicals, redox-active agents
- most important
Define and differentiate: Electrophile, Nucleophile, Redox active reactant, Free radical
- electrophile
- an electron pair acceptor
- positively charged or neutral
- have valent orbitals that are attracted to electron rich centers (aka nucleophile)
- nucleophile
- electron pair donor
- negatively charged
- redox-active reactant
- transfer of electrons between molecules where one loses electrons (oxidation) and one gains electrons (reduction)
- free radical
- contains one or more unpaired electrons
- can accept an electron or give away its lonely electron
How are toxicants with no functional groups (e.g. benzene) detoxicated?
- a function group is added to them followed by conjugation and then catalyzed by phase I enzymes (CYP450)
Define dismutation. Identify the enzyme involved in dismutation of the superoxide radical.
- dismutation: simultaneous reduction and oxidation
- enzyme involved: superoxide dismutase
- catalase (CAT), glutathione peroxidase (GPx), peroxiredoxin (PRx)
Identify two ways by which failure of detoxification can occur.
- when toxicants overwhelm detoxification mechanisms (exhaustion of enzymes)
- inactivation of detoxifying enzymes or reversal of detoxification reactions can occur
- detoxification may produce harmful byproducts
Name the three most relevant target cellular macromolecules/structures for toxicants.
- nucleic acids
- proteins
- membranes
Why is covalent binding an important toxicological reaction?
- it is irreversible –> cells cannot regain function
List the potential effects of toxicants on target molecules.
- dysfunction of target molecules (activation or inhibition)
- destruction of target molecules (crosslinking, fragmentation, degradation)
- formation of neoantigens (altered proteins evoke immune response)
Provide two ways through which toxicants affect the biological microenvironment.
- alter hydrogen ion concentration
- physiochemical alteration of lipid phase of cell membranes
- occupation of a site or a space
Provide an example of a toxicant that affects the biological microenvironment.
- ethylene glycol (antifreeze)
- CO2
- sulfonamides
Provide the two general mechanisms by which toxicants cause cellular dysfunction.
- impairment of cellular regulation
- transcription, translation, signal transduction, extracellular synthesis, apoptosis
- leads to impaired cell division, impaired protein synthesis, apoptosis
- dysregulation of ongoing cellular activity (electrically excitable cells)
- impairment of cell maintenance
- cell death
- impairment of internal cell maintenance
- ATP synthesis
- assembly of macromolecules, membranes, organelles
- regulation of intracellular environment
- impairment of external cell maintenance
- impaired function of integrated systems
What are the ways by which toxicants impair the function of electrically excitable cells?
- alteration of NT levels
- synthesis - hydrazines, decreased GABA
- storage - reserpine, decreased NE, decreased dopamine
- release - botulinum, decreased ACh
- removal - OPs, decreased ACh
- toxicant-NT interactions
- agonism, antagonism, activation, inhibition
- alteration of signal transduction
- activation of Na channels by DDT
- impairment of signal termination
- Barium inhibits Ca activated K channels
What are the three (3) primary cellular impairments that result in cell death?
- ATP depletion
- sustained elevation of intracellular Ca
- overproduction of ROS
- these disorders result in mitochondrial permeability transition (MPT)
- an abrupt increase in mitochondrial inner membrane permeability
What is mitochondrial permeability transition (MPT)? What are its consequences?
- abrupt increase in mitochondrial permeability
- mitochondria swell and rupture, excess Ca released
- consequences
- most of time - necrosis due to ATP depletion
- many times - apoptosis due to caspase activation
- rarely - cell survives due to mitophagy
Name two mechanisms of cell death that do not involve mitochondria.
- damage to plasma membrane
- damage to lysosomal membranes
- destruction of cytoskeleton
- disruption of protein synthesis
Provide two differences between necrosis and apoptosis.
- necrosis
- cell swells, cell becomes leaky and blebs
- lysis causes inflammation
- apoptosis
- cell shrinks, chromatin condenses
- budding
- no inflammation - no lysis, apoptotic bodies are phagocytized
Explain how damage to plasma membranes results in cell death.
- increased permeability means cell can no longer control the passage of ions and water
- cell swells and contents leak out –> toxins able to get in
For each of the following, provide a mechanism by which they are repaired following toxic injury: Oxidized proteins, Peroxidized lipids, Damaged DNA
- oxidized proteins
- reduction – electron gained
- peroxidized lipids
- reductants and enzymes (GSH)
- damaged DNA
- direct repair
- enzymatic reversal of covalent DNA modification, photoreactivation
- excision repair
- base or nucleotide is excised and replaced
- recombination, postreplication repair
- excision of bulky adduct by pyrimidine dimer fails to occur before replication begins
- results in gap opposite dimer in new strand
- recombination with undamaged parental strand fills gap
- direct repair
In which tissue is cellular repair an important strategy to counteract toxic injury? Give a reason why this repair mechanism is important in this tissue.
- peripheral nerves (axons)
- mediated by macrophages and Schwann cells
- allows recovery of function after damage
- need nerves on limbs to do anything
- CNS contains inhibitory glycoproteins and chondroitin sulfate proteoglycans that prevent axonal regrowth
- need to repair bc can’t grow new ones
Name the cells that mediate tissue repair.
- macrophages: remove debris, make cytokines which activate schwann cells
- schwann cells: support growth and synthesize adhesion molecules
Identify three adhesion molecules and their specific functions.
- cadherins: cell-cell adhesions
- connexins: connect cells internally by forming gap junctions
- integrins: cell-ECM adhesions
Name three consequences of repair failure.
- necrosis: injury overwhelms repair
- fibrosis: excess abnormal ECM
- loss of elasticity, compression of normal cells and blood vessels, increases diffusion barriers
- carcinogenesis: failure of DNA repair, apoptosis, or termination of cell proliferation
