Mechanism of Toxicity

7/28/2019 Mechanism of Toxicity

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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.

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Mechanism of Toxicity