Mechanisms of Toxicity 1

Question 1

understanding mechanisms allows

Answer 1

species comparisons
predictions for new compounds
risk assessments

Question 2

determines if there can be a toxic effect

Answer 2

disposition

Question 3

easiest compounds to absorb through membranes

Answer 3

lipid-soluble

Question 4

presystemic elimination can occur at

Answer 4

GI tract

liver

Question 5

pumps that pump toxicants out of cells in the GI tract so they cant reach the systemic system, require ATP

Answer 5

P-glycol proteins

Question 6

produced in the liver to bind specifically to metals

Answer 6

metallothionein

Question 7

many chemicals are released as parent compound that is not toxic, but enzymatic activity changes or metabolizes the parent compound into a toxic compound

Answer 7

toxification

Question 8

compounds that want to take on an extra electron

Answer 8

electrophiles

Question 9

compounds that are willing to donate an electron

Answer 9

nuceophiles

Question 10

what are the potential stages in development of toxicity after chemical exposure

Answer 10

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

Question 11

the transfer of a chemical from the site of exposure, usually an external or internal body surface into systemic circulation

Answer 11

absorption

Question 12

distribution of toxicant to specific target sites may be enhanced by

Answer 12

1. porosity of the capillary endothelium
2. specialized membrane transport
3. accumulation in cell organelles
4. reversible intracellular binding

Question 13

often formed through toxication, very reactive, can cause a lot of damage

Answer 13

free radicals

Question 14

turns radicals into peroxide

Answer 14

superoxide dismutase

Question 15

three enzymes that can detox oxygen radicals

Answer 15

superoxide dismutase
glutathione peroxidase
catalase

Question 16

distributing toxicants to specific sites may be hindered by several processes

Answer 16

binding to plasma proteins
specialized barriers
distribution to storage sites such as adipose tissue
association with intracellular binding proteins
export from cells

Question 17

the removal of xenobiotics from the blood and their return to the external environment

Answer 17

excretion

Question 18

major excretory organs such as kidney and liver can efficiently remove only____

Answer 18

highly hydrophilic usually ionized chemicals such as organic acids and bases

Question 19

three rather inefficient processes for eliminating non volatile, highly lipophilic chemicals

Answer 19

excretion by the mammary gland
excretion in bile in association with biliary micelles or phospholipid vesicles
intestinal excretion

Question 20

reabsorption by diffusion is dependent on

Answer 20

lipid solubility of the chemical

Question 21

radicals are formed by

Answer 21

accepting an electron
losing an electron
hemolytic fission of a covalent bond

Question 22

not only reactive electrophiles but also electron acceptors with the capacity to initiate redox cycling or oxidation of thiols and NADPH

Answer 22

quiniones

Question 23

a free radical of paramount toxicological significance generated by hemolytic fission

Answer 23

hydroxyl radical

Question 24

a relatively uncommon mechanism for activating toxicants

Answer 24

formation of nucleophiles

Question 25

biotransformation that eliminates an ultimate toxicant or prevents its formation

Answer 25

detoxication

Question 26

how are neucleophiles generally detoxified

Answer 26

conjugation at the nucleophilic functional group

Question 27

chemicals without functional groups are detoxified by..

Answer 27

adding a hydroxyl or carboxyl functional group by cytochrome p450 enzyme then an endogenous acid is added by transferase

Question 28

how are electrophilic toxicants detoxified

Answer 28

conjugation with the thiol nucleophile glutathione

Question 29

peroxidase generated free radicals are eliminated by

Answer 29

electron transfer from glutathione

Question 30

detoxication can be insufficient for several reasons

Answer 30

1. toxicants may overwhelm detoxication processes, leading to saturation of the detoxication enzymes 2. reactive toxicant inactivates a detoxicating enzyme 3. some conjugation reactions can be reversed 4. sometimes detoxication generates potentially harmful byproducts

Question 31

interaction of the ultimate toxicant with the target molecule triggers the toxic effect, consideration is given to

Answer 31

1. the attributes of target molecules 2. the types of reactions between ultimate toxicant and target molecules 3. the effects of toxicants on the target molecules

Question 32

what are the attributes of the target molecule

Answer 32

reactivity accessibility critical function

Question 33

what are the outcomes of the target molecule

Answer 33

dysfunction destruction neoantigen formation

Question 34

what are the reaction types with the target molecule

Answer 34

``` noncovalent binding covalent binding hydrogen abstraction electron transfer enzymatic reaction ```

Question 35

to conclusively identify a target molecule as being responsible for toxicity it should be demonstrated that the ultimate toxicant

Answer 35

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

Question 36

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

Answer 36

noncovalent binding

Question 37

practically irreversible this is of great toxicological importance because it permanently alters endogenous molecules

Answer 37

covalent binding

Question 38

an example is hydrolysis by snake venom

Answer 38

enzymatic reaction

Question 39

produced by neutral free radicals

Answer 39

hydrogen abstraction

Question 40

effects caused by the dysfunction of target molecules

Answer 40

``` mimic of receptor ligand inhibition of enzymes blockage of ion channels interference with cytoskeleton break 3D structures of proteins (disulfide bridges) cause DNA damage ```

Question 41

binding of toxicant to protein new protein becomes "non self" may cause autoimmune reaction

Answer 41

neoantigen formation

Question 42

what changes may occur to the microenvironment

Answer 42

no direct interaction with target molecule pH changes destruction of membrane lipids by solvents occupying space