Mechanisms of Toxicity Flashcards
TOX
Define mechanisms of toxicity.
The fundamental chemical and biological interactions responsible for the genesis and longevity of toxic responses.
* Large number of toxicants with numerous biological processes, so ultimately there are numerous potential mechanisms
Why should we study the mechanisms of toxicity?
- To interpret descriptive toxicity data
- We need to understand why one toxicant is more toxic than another.
- To estimate the probability that a chemical will cause harmful effects
- B/c mechanistic studies generate data o doses that ? specific processes.
- To develop procedures to prevent toxicity
- E.g. development of ? is based on understanding mech of toicity. Only possible to reverse toxic resonses if you know how dose repsonses occur and devellpingprocesdures that counteract underlying mechanisms.
- To develop less hazardous drugs and chemicals
– especial;y Selectively toxic chemicals - in order ot reat cancer, drug you are choosing should onyl target cancerous cells without targetting adhjacent normal cells.
Describe the steps in development of toxicosis
- Delivery of toxicant to target site. Once here, interacts with target molecule causing dysfunction or injury leading to toxicosis.
- Alter bio env –> injury –> toxicosis
- Cells impacted by toxicants no longer can perform processes –> toxicosis
Describe delivery of toxicant to target site.
- From site of exposure to the target organ
- Intensity of toxic effect depends on the concentration and persistence of the ultimate toxicant at the site of action
What is an ultimate toxicant?
– The chemical species that reacts with endogenous target molecules or alters the biological microenvironment. The ultimate todxicant can be: Parent xenobiotic-metals, metabolite-Actetaminophen; typically metabolized into? , ROS-Paraquat; during its process of metab, results in prduction of ROS which then discriminately affects cells, Endogenous molecule-Sulfonamides; displaces bilirubin from binding sites in plasma albumin, bili accumulates and is responsible for toxic response.
What factors affect the concentration of the ultimate toxicant at the target site?
Work for toxicant: absorption, etc.
Work against: Distribution (from site of action)
Define the term absorption. What does it depend on?
Absorption
* Transfer of a xenobiotic from site of uptake
to systemic circulation. It depends on:
– Toxicant concentration at site of absorption (GI, resp, skin)
– Surface area of exposure/absorptive site (how much of substance is absorbed).
– Structure of the absorptive surface (thickness)
– Perfusion of the sub-epithelial region
– Physicochemical properties of the toxicant (lipid solubility)
Absorption is counterbalanced by?
Pre-systemic Elimination
* Also known as first-pass elimination
Define pre-systemic elimination.
- It is the loss of a toxicant during transfer from
the site of exposure to the systemic circulation
– Most important for toxicants absorbed from the gastrointestinal tract - May contribute to increased injury of the digestive tract mucosa, liver, and lungs b/c these processes promote delivery to such sites
- Reduces toxicity of toxicants delivered to target sites via systemic circulation.
Describe the process of toxicants
todxicant may be metab by enymes in gut microbiota, gI epi, and excreted befroe absorption.
most important site for pre-sys loss is liver where delviery by hepatic portal vein, fraction of toicant may be metbolized and excrted by bile and ? into GI tract before entering systemic circulation.
Other important site for pre-ssy elimination is lung where sig metab and elimination for toxicant can occur before toxicants enter systemic circulation.
Degrees in thickness of arrows in image is importnt.
Process by which todicants are
Describe the process of toxicants
todxicant may be metab by enymes in gut microbiota, gI epi, and excreted befroe absorption.
most important site for pre-sys loss is liver where delviery by hepatic portal vein, fraction of toicant may be metbolized and excrted by bile and ? into GI tract before entering systemic circulation.
Other important site for pre-ssy elimination is lung where sig metab and elimination for toxicant can occur before toxicants enter systemic circulation.
Degrees in thickness of arrows in image is importnt.
Enterohepatic circ def?
Enterohepatic circulation
Plasma concen. of toxicants that have significant circ is chracte4rizd by? and tertiary peaks over time.
Relisten to this slide.
Describe the process of distribution
Increases toxicant conc. at target site
- Fenestrations: large molecules, even protein bound toxicants, can pass
- Some toxicants can accumulate in organelles. Lysosomes: accumulation occurs via ph trapping and toxicant is protonated in ? lysosome preventing reflux?
Mito = electro = toxicants are protonoated in intermembrane space which has got a high concentration of protons and after are sucked into ? matrix due to strong negativ epotential.
Which mechanisms oppose distribution?
- strong binding delays and prolongs effects and elimination of toxicants.
- Brain caps have very low aqeusou porosity because ? lack ? by extremely tight junctions. BBB prevetns access of hydrophillic chemicals inot brain except those that can be acivelu transported.
- Some chemicals acumulate in tissues where tehy do not exert siginficant effecs. Storage decreased availablity of toxicants to target sites and acts as temporary protective mechanisms.
- Binding to intracelular sites reduces conc. of toxicants at target site. Metals to LMW proteins known as metalll/ When metals bound to this protein they can not inte4ract with sensitiv ttarget sites in cell.
- Toxicants can be found outside cells and can be transported back into EC space which occurs in brain cap endothelial cells in luminal membrane, these cells contain ATP dependent mebrane transpores like ATP binding or ABC transportes such as MDR protein which extrudes chemicals a nd contributes to BBB.
Explain how excretion and reabsorption oppose each other.
Excretion
– Removal of xenobiotics from the blood and their
return to the external environment
* Main organs: kidney, liver → GI tract, lungs
- Primarily excrete hydrophilic or volatile substances.
* Lipophilic substances are not readily eliminated.
Differs from reabsorption in that the Amount of parent compound is reduced by biotransformation.
Reabsorption
– Toxicants excreted in urine, bile & GI secretions may diffuse back/get reabsorbed into blood. REbaospriton depends on lipid solubility and is inversely proportional to the extent of ionization.
Define toxication.
it is a biotransofmrationla reaction in which the ? is more toxic than the xenobiotic.
E.g. conversion of parathion by p450 system into paraoxon increases toxicity of organophosphate?.
Electrophiles are atracted to electrons, toxicants can be converted to nucleophiles as well which are species that are attracted to nucleus becaue nucleus is + charged. Toxicants can cause formation of freee radicals which are molec containing unpaired e- –> highly unstbale and ractive speceis and always require an e- to be stable. toicants can acquire indicsitrimante activity while ? where they are able to donate or accept electrons.
What is detoxication? What does it depend on?
- Biotransformations that eliminate the ultimate toxicant or prevent its formation
- Detoxication mechanisms depend on the nature of the toxicant:
1. Toxicants with no functional groups - Detoxicated by addition of a functional group (-OH, -NH2, -COOH, etc.) followed by conjugation. Then they are …
- Catalyzed by phase I enzymes, e.g., CYP450
– Involves oxidation, reduction or hydrolysis
An endogenous molecule is added by the process of conjugation that is catalyzed by phase 2 enzymes.
- Toxicants with functional groups
– Conjugation (by phase II enzymes)
- Toxicants with functional groups
- Free radicals
– e.g., O2*- is dismutated and converted to water by
catalase (CAT), glutathione peroxidase (GPx) or peroredoxin (Prx) - Protein toxins: Enzymatically inactivated by proteases (e.g. venoms; cleeaved into smaller units, such as dipeptides, that no longer exert toicity.
Dismutation: simultaneous reduction and oxidation
peroxide formed as intermediate which needs to be reduced to water by catalyze or glutothione peroxidase.
When does detoxication fail?
- Toxicants can overwhelm detoxication
mechanisms
– Exhaustion of enzymes, antioxidants, etc - Inactivation of detoxifying enzymes
- Reversal of detoxification reactions
- Detoxication may produce harmful by-products (e.g., conversion of GSH to glutathione thiyl radical)
Describe step 2a: Interaction with Target Molecules
- Toxic action is mediated by the reaction of the ultimate toxicant with target molecules. Such as reactibility, accessibility, and ?
The outcome depends on:
I. Attributes of the target molecules
II. Types of reactions between the ultimate toxicant and the target molecules
III. Effects of toxicant on the target molecules
Describe the dysregulation of electrically excitable cells.
- Alteration of neurotransmitter level
– Synthesis, storage, release, removal - Toxicant-neurotransmitter interactions
– Agonism, antagonism, activation, inhibition - Alteration of signal transduction
- Impairment of signal termination; impairing removal of potassium from cels and proloning excitation of those neuronal cells.
hydrazines impair … etc.
Relisten to this slide.
What are the consequences of MPT?
if few undergo MPT, many undergo MPT, or all/most undergo MPT
At what step does molecular repair fail?
UV-induced thymine dimers
repaired by photoreactivation,
in which energy from visible
light is used to split the bonds
altered base or dimer is recognied by DNAg and is removed leaving the swugar phsphate bone inrac.t this creates a site without a purine or pyrimidine base now as ? recognixed by AP endonuclease. AP dephosphyrlzes the boned and the missing gap is resynthesized by DNA ppol and ? by DNA ligase.
Describe recombinational/postreplication repair.
- Occurs when excision of a
bulky adduct or pyrimidine
dimer fails to occur before
replication begins - This results in a gap opposite
the dimer in the newly
synthesized strand - Recombination with the
undamaged parental strand
fills the gap - Parental strand gap is filled using daughter strand as template
