Mechanisms of Toxicity 1 Flashcards
understanding mechanisms allows
species comparisons
predictions for new compounds
risk assessments
determines if there can be a toxic effect
disposition
easiest compounds to absorb through membranes
lipid-soluble
presystemic elimination can occur at
GI tract
liver
pumps that pump toxicants out of cells in the GI tract so they cant reach the systemic system, require ATP
P-glycol proteins
produced in the liver to bind specifically to metals
metallothionein
many chemicals are released as parent compound that is not toxic, but enzymatic activity changes or metabolizes the parent compound into a toxic compound
toxification
compounds that want to take on an extra electron
electrophiles
compounds that are willing to donate an electron
nuceophiles
what are the potential stages in development of toxicity after chemical exposure
delivery of chemical
interaction with target molecule or alteration of biological environment
cellular dysfunction, injury leading to toxicity
and potentially inappropriate repair and adaption causing toxicity
the transfer of a chemical from the site of exposure, usually an external or internal body surface into systemic circulation
absorption
distribution of toxicant to specific target sites may be enhanced by
- porosity of the capillary endothelium
- specialized membrane transport
- accumulation in cell organelles
- reversible intracellular binding
often formed through toxication, very reactive, can cause a lot of damage
free radicals
turns radicals into peroxide
superoxide dismutase
three enzymes that can detox oxygen radicals
superoxide dismutase
glutathione peroxidase
catalase
distributing toxicants to specific sites may be hindered by several processes
binding to plasma proteins
specialized barriers
distribution to storage sites such as adipose tissue
association with intracellular binding proteins
export from cells
the removal of xenobiotics from the blood and their return to the external environment
excretion
major excretory organs such as kidney and liver can efficiently remove only____
highly hydrophilic usually ionized chemicals such as organic acids and bases
three rather inefficient processes for eliminating non volatile, highly lipophilic chemicals
excretion by the mammary gland
excretion in bile in association with biliary micelles or phospholipid vesicles
intestinal excretion
reabsorption by diffusion is dependent on
lipid solubility of the chemical
radicals are formed by
accepting an electron
losing an electron
hemolytic fission of a covalent bond
not only reactive electrophiles but also electron acceptors with the capacity to initiate redox cycling or oxidation of thiols and NADPH
quiniones
a free radical of paramount toxicological significance generated by hemolytic fission
hydroxyl radical
a relatively uncommon mechanism for activating toxicants
formation of nucleophiles
biotransformation that eliminates an ultimate toxicant or prevents its formation
detoxication
how are neucleophiles generally detoxified
conjugation at the nucleophilic functional group
chemicals without functional groups are detoxified by..
adding a hydroxyl or carboxyl functional group by cytochrome p450 enzyme
then an endogenous acid is added by transferase
how are electrophilic toxicants detoxified
conjugation with the thiol nucleophile glutathione
peroxidase generated free radicals are eliminated by
electron transfer from glutathione
detoxication can be insufficient for several reasons
- toxicants may overwhelm detoxication processes, leading to saturation of the detoxication enzymes
- reactive toxicant inactivates a detoxicating enzyme
- some conjugation reactions can be reversed
- sometimes detoxication generates potentially harmful byproducts
interaction of the ultimate toxicant with the target molecule triggers the toxic effect, consideration is given to
- the attributes of target molecules
- the types of reactions between ultimate toxicant and target molecules
- the effects of toxicants on the target molecules
what are the attributes of the target molecule
reactivity
accessibility
critical function
what are the outcomes of the target molecule
dysfunction
destruction
neoantigen formation
what are the reaction types with the target molecule
noncovalent binding covalent binding hydrogen abstraction electron transfer enzymatic reaction
to conclusively identify a target molecule as being responsible for toxicity it should be demonstrated that the ultimate toxicant
reacts with the target and adversely affects its function
reaches an effective concentration at the target site
alters the target in a way that is mechanistically related to the observed toxicity
due to apolar interactions or the formation of hydrogen and ionic bonds and is typically involved in the interaction of toxicants with targets such as membrane receptors, intracellular receptors, ion channels, and some enzymes
noncovalent binding
practically irreversible this is of great toxicological importance because it permanently alters endogenous molecules
covalent binding
an example is hydrolysis by snake venom
enzymatic reaction
produced by neutral free radicals
hydrogen abstraction
effects caused by the dysfunction of target molecules
mimic of receptor ligand inhibition of enzymes blockage of ion channels interference with cytoskeleton break 3D structures of proteins (disulfide bridges) cause DNA damage
binding of toxicant to protein
new protein becomes “non self”
may cause autoimmune reaction
neoantigen formation
what changes may occur to the microenvironment
no direct interaction with target molecule
pH changes
destruction of membrane lipids by solvents
occupying space
