mechanism of toxicity
TRANSCRIPT
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MECHANISM OF TOXICITY
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ABSORBTION VS PRESYSTEMIC
ELIMINATION
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Absorption is the transfer of a chemical from the site ofexposure, usually an external or internal body surface (e.g.,skin, mucosa of the alimentary and respiratory tracts), intothe systemic circulation.
During transfer from the site of exposure to the systemiccirculation, toxicants may be eliminated. they must firstpass through the GI mucosal cells, liver, and lung beforebeing distributed to the rest of the body by the systemiccirculation
the processes involved in presystemic elimination maycontribute to injury of the digestive mucosa, liver, and lungsby chemicals such as ethanol, iron salts, -amanitin, andparaquatbecause these processes promote their deliveryto those sites.
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EXAMPLE OF XENOBIOTIC ABSOPTION
salicylate and valproate absorbtion bymonocarboxylate transporters
-lactam antibiotics andACE inhibitor drugs bypeptide transporters
Fe2+, Cd2+, as well as some other divalent metalions by the divalent metal-ion transporter,
arsenate by phosphate transporters),
the vast majority of toxicants traverse epithelialbarriers and reach the blood capillaries bydiffusing through cells
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Example OF PRESYSTEMICAL
ELIMINATION
ethanol is oxidized by alcohol dehydrogenase in
the gastric mucosa
cyclosporine is returned from the enterocyte into
the intestinal lumen by P-glycoprotein and is also
hydroxylated by cytochrome P450 (CYP3A4)
morphine is glucuronidated in intestinal mucosa
and liver manganese is taken up from the portal blood into
liver and excreted into bile
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DISTRIBUTION TO AND AWAY TARGET
During distribution, toxicants reach their site or
sites of action, usually a macromolecule on either
the surface or the interior of a particular type of
cell. Chemicals also may be distributed to the siteor sites of toxication, usually an intracellular
enzyme, where the ultimate toxicant is formed.
Some mechanisms facilitate whereas others delaythe distribution of toxicants to their targets.
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Mechanisms Facilitating Distribution
to aTarget
Distribution of toxicants to specific target sites
may be enhanced by
(1) the porosity of the capillary endothelium,
(2) specialized membrane transport
(3) accumulation in cell organelles
(4) reversible intracellular binding
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Mechanisms Opposing Distribution to
a Target
Distribution of toxicants to specific sites may behindered by several processes. The processesinclude
(1) binding to plasma proteins,(2) Specialized barriers,
(3) distribution to storage sites such as adiposetissue,
(4) association with intracellular binding proteins
(5) Export from cells.
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EXCRETION VS REABSOBSTION
Excretion is the removal of xenobiotics from
the blood and their return to the external
environment. Excretion is a physical
mechanism
Reabsorption is the opposite of excretion, the
xenobiotics back to the bloodstream from
urine or GI tract
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Reabsorption by diffusion is dependent on thelipid solubility of the chemical
Acidification of urine favors the excretion of weak
organic bases, whereas alkalinization favors theelimination of weak organic acids
Some organic compounds may be reabsorbedfrom the renal tubules by transporters, ex some
-lactam antibiotics and angiotensin convertingenzyme inhibitor drugs across the brush bordermembrane with peptide transporters (PEPT)
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compounds secreted into bile are usually organic acids,their reabsorption is possible only if they aresufficiently lipophilic or are converted to more lipid-
soluble forms in the intestinal lumen Ex glucuronides of toxicants such as diethylstilbestrol,
and glucuronides of the hydroxylated metabolites ofpolycyclic aromatic hydrocarbons, chlordecone, andhalogenated biphenyls are hydrolyzed by the -glucuronidase of intestinal microorganisms, and thereleased aglycones are reabsorbed
Glutathione conjugates of hexachlorobutadiene andtrichloroethylene are hydrolyzed by intestinal and
pancreatic peptidases, yielding the cysteine conjugates,which are reabsorbed and serve as precursors of somenephrotoxic metabolites
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TOXICATION VS DETOXICATION
A number of xenobiotics (e.g., strong acids andbases, nicotine, aminoglycosides, ethylene oxide,methylisocyanate, heavy-metal ions, HCN, CO)
are directly toxic, whereas the toxicity of others isdue largely to metabolites
Biotransformation to harmful products is calledtoxication or metabolic activation
Biotransformation that eliminates an ultimatetoxicant or prevents its formation is calleddetoxication
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several pathways of toxication
This increased reactivity may be due to
conversion into
1) electrophiles,
2) free radicals,
3) nucleophiles,
4) redox-active reactants
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Formation of Electrophiles
Electrophiles are molecules containing an
electron-deficient atom with a partial or full
positive charge that allows it to react by
sharing electron pairs with electron-richatoms in nucleophiles
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Formation of Free Radicals
A free radical is a molecule or molecular
fragment that contains one or more unpaired
electrons in its outer orbital.
Radicals are formed by (1) accepting an
electron or (2) losing an electron, or by (3)
homolytic fission of a covalent bond.
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Formation of Nucleophiles
The formation of nucleophiles is a relatively
uncommon mechanism for activating
toxicants
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Formation of Redox-Active Reactants
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Detoxication can take several pathways, depending onthe chemical nature of the toxic substance
1) Detoxication of Toxicants with No Functional Groups
2) Detoxication of Nucleophiles3) Detoxication of Electrophiles
4) Detoxication of Free Radicals
5) Detoxication of Protein Toxins
When Detoxication Fails Detoxication may beinsufficient
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Toxicity is typically mediated by a reaction of
the ultimate toxicant with a target molecule
a series of secondary biochemical events
occur, leading to dysfunction or injury that is
manifest at various levels of biological
organization, such as at the target molecule
itself, cell organelles, cells, tissues and organs,and even the whole organism
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Attributes of Target Molecules
The identification and characteristics of the
target molecules involved in toxicity constitute
a major research priority
most prevalent and toxicologically relevant
targets are macromolecules such as nucleic
acids (especially DNA) and proteins
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To be a target an endogenous molecule :
must possess the appropriate reactivityand/or steric configuration to allow the
ultimate toxicant to enter into c must be accessible to a sufficiently high
concentration of the ultimate toxicantovalent
or noncovalent reactions mechanistically related to the observed
toxicity (critical function)
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Types of Reactions
1. Noncovalent Binding
2. Covalent Binding
3. Hydrogen Abstraction4. Electron Transfer
5. Enzymatic Reactions
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Effects of Toxicants on Target
Molecules
Dysfunction of Target Molecules
Destruction of Target Molecules
Neoantigen Formation
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Toxicity Not Initiated by Reaction with
Target Molecules
1. chemicals that alter H+ ion concentrations in theaqueous biophase, thus dissipating the protongradient that drives ATP synthesis
2. solvents and detergents that physicochemically
alter the lipid phase of cell membranes anddestroy transmembrane solute gradients thatare essential to cell functions
3. other xenobiotics that cause harm merely by
occupying a site or space ex, Carbon dioxidedisplaces oxygen in the pulmonary alveolarspace and causes asphyxiation
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Toxicant-Induced Cellular
Dysregulation
Dysregulation of Gene Expression
Dysregulation of Signal Transduction
Dysregulation of Extracellular SignalProduction
Dysregulation of Ongoing Cellular Activity
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Toxic Alteration of Cellular
Maintenance
Impairment of Internal Cellular Maintenance:
Mechanisms of Toxic Cell Death
Impairment of External Cellular Maintenance
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REPAIR AND ADAPTATION
Mechanism of repair
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Mechanisms of Adaptation
adaptation to toxicity may result from biologicalchanges causing
1) diminished delivery of the causative chemical(s)to the target,
2) decreased size or susceptibility of the target
3) increased capacity of the organism to repair
itself,4) strengthened mechanisms to compensate thetoxicant inflicted dysfunction
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An organism has mechanisms that
1) counteract the delivery of toxicants, such as
detoxication
2) reverse the toxic injury, such as repair
mechanisms;
3) offset some dysfunctions, such as adaptive
responses.