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
