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Tox 300 midterm 1 > Metabolism (biotransformation) > Flashcards

Metabolism (biotransformation) Flashcards

1
Q

Biotransformation:

A

the enzyme0 catalyzed conversion of one xenobiotic into another.

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2
Q

what is an induced example?

A

the more you abuse alcohol or drug abuse the more of a higher dose you need to get the same response because the alcohol or drug is metabolized faster then more you are exposed to it.

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3
Q

describe the first pass effect:

A

drugs that are absorbed from the gut may be biotransformed by enzymes in the gut wall and liver before reaching the systemic circulation. This process lwoers their degree of bioavailibity and is the first line of defense.

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4
Q

define oxidation:

A

added oxygen to molecule to try and make it more soluble to get rid of from the body.

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5
Q

why can it be bad if a cyp is inhibited or blocked?

A

if the enzyme responsible to biotransform that xeno to a more soluble xeno is blocked then thats bad because the drug will stay in the body for a long time and then as the quote goes, the dose defines the poison, becomes very important.

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6
Q

describe enzyme induction and inhibition:

A

if you induce an enzyme that produces an active metabolite and you will have a greater possibility of toxic affect. If you block that enzyme that gets ride of toxic metabolites ou can also get a toxif effect.

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7
Q

what are the type of metabolites they measure in atheletes?

A

glucuronidation

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8
Q

what is the significance of induction:

A

if you have induction of a metabolite that induces a reactive metabolite then that can be very signficant

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9
Q

what is the enzyme and co factor of sulfation?

A

enzyme: sulfotransferase Co factor: PAPS

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10
Q

how can GST reverse the sad face pathway?

A

GST can biotransform that toxic electorphile and turn it back into something soluble.

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11
Q

how can we get ride of a very lyphphilic molecule?

A

biotrasnform it to become more water soluble and so we can excrete t!

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12
Q

describe the CYP superfamily:

A

very versatile nezymes, its not a lock and key fit, they can recongize a wide variety of substrates and biotransform them which is great for humans who invent new shit all the time!

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13
Q

enzyme and co-factor of glucuronidation

A

enzyme: UDP- glucuronosyl transferase (UDP-GT) Cofactor: UDP-glucuronic acid

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14
Q

acetominophen does not need to go through phae one because….

A

the hydroxl group has been exposed already.

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15
Q

Draw sulfation:

A
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16
Q

what phase 2 enzyme is one of our most important defensives towards reactive elctrophiles?

A

Glutathione conjugation

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17
Q

what is the hardest chemical to excrete?

A

super hydrophobic molecules! they are so stable and super hard to excrete! They are very hard to metabolize!

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18
Q

draw a aliphatic hydroxylation

A
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19
Q

when can inhibition be good>

A

if you inhibit the biotransformation of a toxic metabolite

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20
Q

how does sex, age and diet play a role?

A

some of the enzymes are sex specific. Additionally, age of the animals gives different susceptibilities. Young ones are much more susceptible. Many things in our diets are able to induce or inhibit phase 1 and phase 2 enzyms with an example being grapefruit juice!

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21
Q

what determines the half life of the xenobitoic?

A

biotransformation!

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22
Q

what happens during the sad face pathway of Acetaminophen

A

Cytochrome P450–? N acetyl-p-benzoquinoeimine (NAPQ)(electrophile) - this binds to hepaticc proteins leading to centrilobular necrosis - CYP2E1 is induced by ethanol, ethanol inhibits protein syntehsis - so do not take tylenol for a hangover

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23
Q

phase 2 enzymes can also be what?

A

induced or inhibited.

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24
Q

what is the second easiest chemical to excrete?

A

a chemical that is somewhat polar, it alreadys has a hydroxyl group on it so can skip phase 1 and go to phase 2!

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25
Q

describe interspecific differences

A

differences between species are always present in the biotransformation of xenobiotics. Higher vertebrates have the greatest xenobiotic metabolism the n lower vertebrates.

26
Q

describe parathion:

A

parathion gets bioactivated into paraoxon which is an insecticide. so insects absorbs parathion, bioactivates it to paraoxon which kills them! We bioactivate it to but we have much different surface t volume ration and so it is more accumulated in an isnect.

27
Q

The activity of cyp enzymes is not static: they can be 2 things

A

induced or inhibited

28
Q

draw an aromatic hydroxylation

A
29
Q

what is the most important phase of conjugation reaction?

A

glucuronidation because of its ability to recognize lots of different xens.

30
Q

as you increase the dose of Acetaminophen what happens?

A

we start to deplete GST as it drops the amount of covalent binding to your proteins take off!

31
Q

what is a classic example of inhibition:

A

grapefruit juice. contains naturally occuring xenobitoics called furanocoumarins. extremely potent inhibitors of CYP3A4. In humans this is the most important live transformation enzyme because it recognizes lots of different substrates. So if yuo take a drug that relies on tis enzyme and you drink grapefuit juice that drug will stick around for a long time and once again the dose defines the poison

32
Q

phase 2 is called conjugation reactions, define:

A

they attach a very water soluble group to the xeno so it can be excreted from the body. They basically add sugar.

33
Q

bioactivation:

A

biotransformation results in a more toxic metabolite

34
Q

what is the general hydroxylation reaction:

A

RH (substrate or xenobiotic) + O2 + NADPH — CYP—–> ROH (product metabolite) + H2O+ NADP+

35
Q

how is phase 2 used for atheletes?

A

because pf this they can measure the urine for drugs because of the sugar group.

36
Q

what ar the different things that can happen during phase 2?

A

sulphation, glucuronidation, glutathione conjugation and acetylation

37
Q

Oral bioavailibility:

A

the fraction of an orally administered xenobiotic that reaches the systemic circulation in an unchanged form.

38
Q

where in our body is there high biotransformation and low biotransformation?

A

high in the liver! Very low in the nervous system which is another way to protect us since some xenbitoics can be pretty toxic.

39
Q

cytochrome p450 is located where?

A

smooth endoplasmic reticulum

40
Q

how can phenacetin get bioactivated for good/

A

acetominophen is an amazing pain reducer and phenacetin is not as good but can get bioactivated to become acetaminphen and a very good pain reducer.

41
Q

epoxide:

A

the O in the oxidative step. it is desperatly trying to find an electron. If it finds that electron in DNA or protein it creates something that is toxic.

42
Q

enzyme and co factor for acetylation:

A

enzyme: acetyltransferase Co- factor: acetyl- CoA

43
Q

define the duration of action using the difference in how long it takes different animals to wake up

A

the reason for this species difference is the relative enzyme activity in the liver! the mouse has a really high enzyme activity so it wakes up very quickly whereas the dog is a very lowe enzyme activity.

44
Q

why is lipophilicty bad>

A

you’ll basically never get rid of it! when the xeno gets filtetered at the glomerulus to be excreted it is reabsorbed.

45
Q

why do you never give cats acetaminophen?

A

becasue they are poor glucuronidation they don’t really express this and this is what you need to biotransform it and get rid of it.

46
Q

Draw glucoronidation

A
47
Q

Glutathione enzyme and co factor:

A

Enzyme: Glutathione S-transferase (GST) and co factor: glutathione (GSH)

48
Q

what is the easiest route for excretion?

A

the hydrophilic route is easy because it is already soluble and can just be excreted.

49
Q

what are the 5 genetic and environmental factors influencing biotransformation:

A

1.) enzyme induction and inhibition 2. Intraspecific differences 3. Interspecific differences 4.) sex, age and diet 5.) underlying pathology (disease)

50
Q

describe intrapsecific differences:

A

humans are a great example. you will always have peopke who respond differently to drugs. some lower and some more sensitive! This is due to enzyme polymorphism. Alcohol dehydrogenze (ADH) a certain subset of human beings are poor metabolisms of alcohol.

51
Q

what is the third easiest chemical to excrete?

A

hydrophobic molecules, these will have to go through phase 1 and phase 2.

52
Q

Glutathione is important in what organ?

A

liver! It would represent 5% of all the proteins in your liver!

53
Q

Phase 1 has one major step

A

oxidation

54
Q

what is this?

A

Glutathione

55
Q

describe how cytochrome p450 is really important in phase 1:

A

is add or expose a polar functional group on the xenobiotic. A polar functional group is an -OH, NH2 and COOH. They are polar because they are water soluble groups.

56
Q

draw acetylation:

A
57
Q

what will determine if a xenobitoic can be excreted?

A

the chemical features like their lipohilicity

58
Q

detoxification:

A

biotransformation results in a less toxic metabolite

59
Q

define and secirbe the 3 different kinds of inhibition:

A

1.) competitive: the inhibitor competes with the substrate to get into the space of the enzyme 2.) non-competitive: the inhibotr doesnt have an affinity for the active site but actually interacts with another site on the enzyme that changes the enymes conformation every so slightly that the substrate lock and key does jot fit on the subtrate anymore and therefore it blocks it in a passive way. 3.) Suicide: the xenobitoic gets metabolized by CYP and it produces a reactive metabolite. that molecule also binds to the enzyme but binds super strongly with a convalent bond and is irreversible and that enzymes dies!

60
Q

what are the two most signifncat enenzymes for cytochrome p450?

A

two most significant enzymes being CYP3A4 and CYP2D6

Tox 300 midterm 1 (5 decks)

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