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PCL201 > Lec 10, 11, 12 - Drug Biotransformation > Flashcards

Lec 10, 11, 12 - Drug Biotransformation Flashcards

1
Q

explain the detoxification of doxorubicin including:

  1. what can it get converted into and by which enzyme
  2. which of the byproducts are cytotoxic? Why?
A
  1. quinone fg either converted to semiquinone by nadph cytochrome p450 reductatse (1e reduction rxn), or to hydroquinone by quinone reductase (2e reduction)
  2. semiquinone and radical oh, because they contain a radical atom
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2
Q

what are reduction reactions? are they phase 1 or phase 2?

A

rxns where the product gets reduced (gets electrons)
phase 1

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3
Q

which functional group in doxorubin do reductases act on?

A

quinone

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4
Q

t/f: all enzymes will carry out the same effect on a drug

A

false

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5
Q

is hydrolysis a phase 1 or 2 reaction?

A

1

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6
Q

what are epoxides and how does hydrolysis combat toxicity?

A

chemically reactive electrophillic molecules, covalently bidn to proteins and lead to cytotoxicity
conjugates epoxide with water, gets rid of three ring reactive o and replaces with 2 oh groups

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7
Q

what is the difference between microsomal and cytosolic forms of enzymes?

A

microsomal found in ER
cytosolic found in cytosol

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8
Q

epoxide hydrolases convert epoxides into what? why is this byproduct less reactive?

A
  • dihydrodiol (breaks open o ring and adds 2 hydroxyl)
  • less reactive because less strain from 3 ring
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9
Q

what is the main goal of phase 2 reactions?

A
  • want to make the molecule more water soluble.
  • some cellular pathway leads to the formation of endogenous substances that get tacked onto the drug via a transferase
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10
Q

how is a glucuronide metabolite formed

A

UGT tacks glucouronic acid onto the drug

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11
Q

generally speaking what is glucoronidation

A

transfer of glucauronic acid onto a drug

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12
Q

what enzyme carries out glucoronidation? how many? where?

A

udp glucoronosyltransferase (UGT) - we have 22. happens inside er

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13
Q

what are the substrates for UGT (ie: where does it attach to)? what drugs contain these groups?

A

hydroxyl, carboxyl, amine, sulfhydryl
acetominophen, morphine

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14
Q

what is the cofactor for glucoronidation? which part of this cofactor actually gets attached to the drug to make the glucoronide metabolite?

A

UDPGA
just the gluc. acid gets attached

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15
Q

explain how a glucouronide metabolite is formed, including the steps of UDPGA synthesis

A

utp joins with g1p
utp dephos by udp glucose pyrophos
udp glucose oxidised by nad and h20, makes udp nadh, h
udp gluc crosses into luman
drug joins into UDPGA, UDP separated
udp into cyto and gets phosphorylated intto UTP, process restarts

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16
Q

explain the roles of the following enzymes:
1. UDP glucose pyrophosphorylase
2. UDP Glucose dehydrogenase
3. UDP Glucoronosyl transferase

A
  1. joins UTP and glucose 1 phos
  2. oxidises udp gluc
  3. transfers GA onto drug
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17
Q

UGT action occurs on the lumenal or cytoplasmic side?

A

lumenal

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18
Q

how is glucoronidation impacted in gilberts symptom?

A

inherited deficiency in the glucuronidation of endogenous bilirubin, resulting in its accumulation and jaundice, mild disorder, 2-5% of pop

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19
Q

how is glucoronidation impacted in crigler-najjar syndrome?

A

UGT deficiency -> billirubin buld up -> impaired drug clearance and hyperbilli -> aplastic anemia from chloramphenicol -> grey baby syndrome

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20
Q

how does chloramphenical lead to grey baby syndrome?

A

The gray baby syndrome is a type of circulatory collapse that can occur in premature and newborn infants and is associated with excessively high serum levels of chloramphenicol, chlo not broken down by glucoron. bc of genetic deficiency

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21
Q

what is the end goal of glutathione conjugation?

A

attach cysteine (with sulfur) to drug for increased excretion

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22
Q

t/f: the whole glutathione molecule gets added to the drug in glutathione conjugation

A

false, just the cysteine

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23
Q

give a general overview of what glutathion conjugation is (the pathway) and how it leads to excretion?

A

drug joins onto tripeptide S with glutathion s transferase,

gammaglutamyltranspeptidase takes off and recycles the glutamine

cysteinyl glycinase takes off and recyvles the GLY

acetyltransferase attaches acetyl to cystein drug complex

now mercapturic acid, more water sol, excreted in urine

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24
Q

where does glutathione conjugation occur?

A

cytosol, mitochondria, microsomal

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25
Q

what is the role of glutaythione s transferase in glut. conj?

A

attached the drug to tripeptide

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26
Q

glut. conj is carried out on which substrates? functional group examples include?

A

electrophillic centres (epoxides, arene oxides, nitro groups, hydroxylamines)

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27
Q

what is the cofactor in glut. conj? which part actually gets attached to the drug?

A

GSH (reduced glutathione) (glu, cys, gly), - just the cysteine

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28
Q

t/f; one enzyme is responsible for the entire glut. conj. pathway

A

false

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29
Q

what happens to the y-Glc-AA and Gly in glut. conj?

A

they get recycled

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30
Q

what is the end goal of sulfation?

A

attach sulfate to drug

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31
Q

what enzyme carries out sulfonation and how many do we have?

A

sulfotransferase (SULT), 14

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32
Q

where does sulfonation occur

A

cytosol

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33
Q

what substrates does sulfonation act on? drug examples?

A

phenols, alipathic alcohols
acetaminophen, steroid hormones

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34
Q

what is the cofactor for sulfonation? does the whole thing get attached to the drug? how is this cofactor formed?

A
  1. PAPS (3 phosphoadenosine 5 phosphosulfate)
  2. no, just the sulfate
  3. sulfate joins with atp via atp sulfurylase, forms aps
    aps phosphorylated, forming paps
    sult removes pap, attaches sulfate to drug
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35
Q

t/f: only one phase 2 reaction occurs on each drug

A

false

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36
Q

what does acetominophen heptatoxicity demonstrate about phase two reactions?

A

many phase 2 rxns can happen on same drug, all wont have beneficial effects

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37
Q

explain the inactivation pathways of acetominophen, and what happens when these pathways get overwhelmed

A

either via glucoronidation or sulfonation. when overwhlemed, makes reactive intermediate napqi via p450s cyp2e1 and cyp3a4.

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38
Q

what is the backup detox pathway of acetominophen if glucoronidatoion and sulfation get occupied

A

GSH conjugation: addition of cysteine to napqi for excretion via glutathione s conjugation

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39
Q

how does NAC restore glutathione levels

A

its a cysteine precursor

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40
Q

what is NAPQI, how is it formed, and when would liver cell death occur

A

n-acetyl- p - benzoquinoneimine
formed when normal inactivation pathways of acetaminophen are full
liver cell death happens when napqi cant go through detox path, and it joins onto other macromols

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41
Q

what is the end goal of acetylation

A

add acetyl group onto drug

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42
Q

what enzyme carries out acetylation

A

n-acetyl-transferase (NAT)

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43
Q

how many NATs do we have?

A

2

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44
Q

where does acetylation occur

A

cytosol

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45
Q

what substrates does acetylation occur with? drug examples

A

aromatic amines and hydrazine
isoniazid, sulfamethoxazole

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46
Q

what cofactor is necessary for acetylation?how is this cofactor made? does the whole thing get attached to the drug?

A

acetyl coA
acetate joins onto coa
only acetyl gets attached, via NAT

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47
Q

what is the end goal of methylation?

A

attach a methyl group to the drug

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48
Q

what enzyme (general) carries out methylation? is there only one subtype?

A

methyltransferase
no
COMT, TPMT

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49
Q

where does methylation take place?

A

cytosol

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50
Q

what substrates does methylation use? why these substrates? drug examples?

A

phenol, catechol, alipathic and armoatic amine, n-heterocyclic, sulfhydryl

levodopa, 6mp

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51
Q

what cofactor is involved in methylation? does the whole thing get attached to the drug?

A

s-adenosylmethionine (SAM)

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52
Q

how is the methylation substrate formed?

A

methionine joins atp, makes sam and ppi, pi

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53
Q

what role does TPMT play?

A

transfers methyl from sam onto drug

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54
Q

does methylation detox or activate 6 mercap?

A

detox

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55
Q

what does 6 mercaptopurine get turned into, and by which rxn? what type of drug?

A

6 -methylmercaptopurine, by methylation via TMPT, cancer (leukemia) drug

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56
Q

what patient consideration is important when giving 6 mercap?

A

genetic polymorphs: do they have function tmpt to be able to detox cancer drug

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57
Q

what factors affect drug biotransformation

A

induction and inhibiton
diet
species
age
sex
hormones
disease states
genetics

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58
Q

t/f: individuals have the same capacity for drug met. throughout their lives

A

false

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59
Q

what does it mean to induct or inhibit an enzyme

A

induct: activate it
inhibit: block it

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60
Q

how can efficacy of drug be affected by induction/inhibtion

A

induction: may speed up drug met, negating or increasing effect dep on drug
inhibition: slows down drug met, causing slower elim, or less prodrug activation

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61
Q

how can toxicity of drug be affected by induction/inhibtion

A

induction: may lead to toxic byproducts
inhibition: not enough prodrug met, leads to tox

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62
Q

what does therpaeutic index have to do with impacts of induction/inhibition

A

narrow thera, need to understand how things that may induce or inhibit drug met may impact conc (very close between beneficial and toxic)

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63
Q

what does it mean for a p450 to be strongly inducible?

A

it can easily be activated

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64
Q

which is the most abundant p450? how is it induced?

A

cyp3a4/5. induced by pregnane x recep activation

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65
Q

this p450 metabolizes caffeine and is induced by cigarettes and charcoal broiled meats

A

cyp1a2

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66
Q

this p450 is induced by alcohol intake

A

cyp2e1

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67
Q

explain the relationship between aryl hydrocarbon receptors and p450s

A

activation of aryl hydrocarbon recepts can go on and induce p450s

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68
Q

what type of molecules have high affinity for aHr?

A

flat, cyclic, cl

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69
Q

TcdD, Indol[3,2,b]carbazole, 3methylcholanthrene, and benzo[a]pyrene are all examples of what

A

inducers of ahr

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70
Q

explain what it means to say that benzoapyrene induces its own biotransformation? what experimental evidence shows this?

A

the more benzoapyrene you have, the more benzoapyrene gets metabolized

the experiement where they injected mice microsomes with different levels of benzoa: dep on how much they had in their livers, the benzo was metabolised at different rates.

induction is reversible

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71
Q

why do smokers see a higher level of cyp1a1 activity?

A

cig smoke contains BP, activates ahr, activates cyp1a1

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72
Q

in which stage of enzyme modification does the most enzyme regulation occur?

A

gene transcription

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73
Q

at which stages can enzymes be regulated?

A

gene transcription, processing, mrna stab, translation, enzyme stabalization and degradation

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74
Q

cyp1a2 is regulated in which stage

A

processing

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75
Q

cyp2e1 is regulated in which stage

A

translation

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76
Q

which cyps are regulated in enzyme stabalization and degradation phase

A

2e1, 3a1, 3a2, 3a6

77
Q

explain how an inducer leads to increased biotransformation (the whole pathway)

A

inducer goes into cell, attached to ahr along with chaperons, goes into nucleus via arnt, compex can activate phase 2 gst and ugt of p450s (1a1, 1a2, 1b1, 2s1), which increases biotrans

78
Q

t/f: inducers only impact p450 action

A

false, also impact phase 2 ugt, gst

79
Q

order these steps:
1. tcdd enters cell
2. p450s and phase 2 gst ugt get activated
3. chaperones hsp90 and aip join onto ahr tcdd complex
4. hsp unattaches, ARNt joins to AHR TCDD complex
5. AHR TCDD COMPLEX and chaperons enter nucleus
6. increased drug biotransformation

A

1, 3, 5, 4, 2, 6

80
Q

what is the pregnane x receptor?

A

another receptor whos activation can induce p450s

81
Q

how does st johns wort lead to increased metabolism of drugs? by which receptor?

A

joins onto pxr with chaperons, enters nucleus, induces cyp3a4 gene

82
Q

t/f: increased metabolism of drugs is always bad

A

false

83
Q

how does induction by phenobarbital help neonates with hyperbillirubinemia

A

induces UGT, which clears billirubin through glucoronidation

84
Q

contrast therapeutic vs prophylactic

A

therapeutic is responsive, prophylactic is preventitative

85
Q

how does induction by indole 3 carbinol provide reduced risk for breast cancer? why?

A

binds to ahr, induces cyp1a2, cyp1a1, turns estradiol into reduced form, non toxic and readily elim.

86
Q

how does 13c reduce breast cancer risk?

A

reduces circulating levels of 17B estradiol

87
Q

is the 2-oh or the 4-oh the more readily excreted estradiol

A

2-oh

88
Q

treatment with ddt and subsequent less mammary tumours tells us what about the relationship between ddt and dmba?

A

ddt protects from dmba carcinogen

89
Q

how does ddt provide dmba protection

A

enhances first pass clearance of dmba

90
Q

t/f: inducers only induce one p450 species

A

false - they can induce more than one

91
Q

t/f: inducers only induces p450s

A

false - can induce some phase 2

92
Q

t/f: inducers never stimulate their own metabolism

A

false: can stim own (benzopyrene ex)

93
Q

t/f: inducers can stimulate themselves and several other chemicals

A

true

94
Q

t/f: inducers are active only in mammalian species

A

false; also in non mam

95
Q

t/f: inducers only act in one given tissue at a time

A

false, act in many

96
Q

t/f: inducers usually slow the rate of a certain p450s transcription

A

false, usually speed it up

97
Q

explain the issues around the drug seldane in regards to inhibition

A

seldane metabolism was inhibited when taken with erythromycin and ketoconazole, therefore never got converted from terfenadine

98
Q

how does terfenadine affect the heart

A

clocks k+ channels, leading to qt prolongation, and torsades de pointes

99
Q

what is torsades de pointes

A

arrythymia

100
Q

t/f: the metabolism of terfenadine leads to torsades de pointes

A

false - the blockage of metabolism does

101
Q

what impact does erythromycin or ketconzale have on terfenadine

A

blocks its metabolism into fexofenadine, leading to torsades de pointes

102
Q

why is allegra (fexofenadine) the preferred antihistamine

A

because it directly leads to antihistamine benefits, not reliant on metabolism that may be blocked

103
Q

t/f: cyp3a4 is only involved in one metabolic pathway

A

false

104
Q

why can cimetidine not be taken with wafarin, theophylline or phenytoin

A

drug drug interactions may occur because it may inhibit their metabolism

105
Q

explain the metabolic bottleneck

A

too many drugs trying to go into one recep, recep cant handle them all, they dont all get appropriately metabolised

106
Q

t/f: only drug interactions inhibit metabolism

A

false - diet, enviro, etc can as well

107
Q

whats the relation of grapefruit and cyp3a4

A

grapefruit inhibits metabolism via cyp3a4

108
Q

why is it important to know the specific p450 that metabolises a drug

A

so you can predict what factors might impact the metabolism of the drug

109
Q

what is METEOR

A

a system to determine which p450 acts on which drug

110
Q

what is species extrapolation

A

extrapolating how a drug may act in a human based on how it acts in an animal

111
Q

what are concerns with p450 function exptrapolation from animal models?

A

the same genes in human vs animal dont always have the exact same function

112
Q

contrast the two types of invitro tests to test p450 function

A

test in human tissues, or clone human ezyme into an animal and test (need to include p450 reductase)

113
Q

what are the three steps to reaction phenotyping (xenotech approach)

A

find the p450s expressed in the cdna ,
correlation analysis with hlm from different ppl
inhibition of enzymes, see which one affects metabolism

114
Q

what does the cdna bar plot show in reaction phenotyping?

A

the relative abundance of how each p450 metabolises the drug

115
Q

what does the correlation in hlm plot show in reaction phenotyping

A

how much of the activated drug forms based on the activity of a certain enzyme (is there a correlation - this would be done for each enzyme that you get in the cdna plot)

116
Q

what can you use as a predictor of enzymatic activity on an hlm scatterplot

A

how much a certain substrate gets acted on

117
Q

what does the inhibition plot tell you in reaction phenotyping??

A

when you inhibit each of the enxymes, what happens to the prodrug metabolism? if the drug gets metabolised less when a certain p450 is inhibited, that means that that p450 is involved in its metabolism

118
Q

explain what “ can do != will do” means in reaction phenotyping, and exceptions to this rule

A

just because it does something in vitro, does not mean it always will invovo. unless: you use the right concentration of substrate, all pathways are considered, and each individual enzymes variation is considered.

119
Q

why dont pharm companies want cyp3a4 to be the primary route of metabolism for a new drug?

A

cyp3a4 metabolizes so many drugs, therefore lots of competing pathways. highly variable, and many possibilities for it to be induced and or inhibited.

120
Q

why dont pharm companies want cyp2d6 to be the primary route of metabolism for a new drug

A

lots of polymorphism – variations in metabolism

121
Q

whats a limitation of in vitro tests to predict drug metabolism

A

only show the potential enzymes that metabloize the drugs, not everything

122
Q

what are the key issues when dealing with predicting drug met.

A

need to know all enzymes that are able to metabolise, all enzymes present, and all activity of enzymes

123
Q

how can you figure out ratios of metabolic enzymes from probe drugs

A

See what metabolites are created, use that to figure out which enzymes are active

124
Q

which p450 is heavily induced by alcohol intake, expressed in liver, kidney, lung, and some extrahepatic tissues, and biotransforms ethanol and halgenated alkanes?

A

cyp2e1

125
Q

which p450 converts benzene and chloroform into heptotoxic metabolites

A

cyp2e1

126
Q

which p450 was originally discovered as microsomal ethanol oxidsising system

A

cyp2e1

127
Q

what is a polymorphic gene

A

one gene, many variations

128
Q

which p450 has low abundance but biotransforms antiarrythmics, antidepressants, antipsychotics, bblockers, analgesics

A

cyp2d6

129
Q

propafenone is a

A

antiaryhtmia drug

130
Q

fluoxetine is a

A

antidepressant

131
Q

chlropromazine is a

A

antipsychotic

132
Q

propranolol is a

A

beta blocker

133
Q

codeine is a

A

analgesic

134
Q

which p450 is mainly expressed in the liver, polymorphic in humans, and catalyzes hydroxylation of s-mephenytoin

A

cyp2c19

135
Q

s-mephenytoin is a

A

anticonvulsant

136
Q

what is the main 2c enzyme in the liver

A

cyp2c9

137
Q

which p450 is found in the liver, polymorphic, and catalyzes hydroxylation of tolbutamide, phenytoin, and warfarin

A

cyp2c9

138
Q

tolbutamide is a

A

hypoglycemic

139
Q

phenytoin is a

A

anticonvulsant

140
Q

warfarin is a

A

anticoagulant

141
Q

_____ is expressed in the liver, but not extrahepatically. its relative ____ is not in the liver, but is in other tissues

A

cyp1a2, cyp1a1

142
Q

what induces cyp1a2

A

polycyclic aromatic hydrocarbons

143
Q

what does cyp1a2 biotransform

A

caffiene, acetaminophen, aromatic amine carcinogens, aflatoxin

144
Q

what is the most abundant p450 in the liver and small intestine

A

cyp3a4

145
Q

which two enzymes catalyze 50% of known drugs

A

cyp3a4/3a5

146
Q

erythromycin, codeine, lovastatin, diazepam, and taxol are all metabolized by:

A

cyp3a4

147
Q

what is the main p450 in the human fetal liver

A

cyp3a7

148
Q

t/f: only a limited range of xenobiotics induce cyp3a4

A

false

149
Q

p450s were discovered by:

A

omura, sato

150
Q

what does the 450 in p450 represent

A

wavelength og light that the heme group in the prtein absorbs

151
Q

what is a microsome

A

circular vesicle formed from ER membrane after centrifugation

152
Q

can microsomes be found in living cells

A

no

153
Q

what did ronald estabrook show

A

that cytocrhom p450 metabolizes drugs and steroids

154
Q

whats the main reaction carried out by cytochrome p450

A

monooxygenation (adding in an o and forming a water)

155
Q

what type of protein are cytochrome p450s

A

heme

156
Q

ferric vs ferrous

A

ferric = 3+
ferrous = 2+

157
Q

what form must iron be in to bind oxygen

A

ferrous

158
Q

which form of iron is reduced: ferric or ferrous

A

ferrous

159
Q

which part of the p450 binds to the substrate

A

fe3+

160
Q

overall p450 rxn

A

RH + o2 + nadph + h -> roh + h20 + nadp

161
Q

order these steps:
1. p450 containing ferric iron binds the substrate
2. the ferrous p450 iron binds an oxygen
3. the o-o bond splits
4. the carbon radical and hydroxyl radical recombine. the hydroxylated metabolite is released
5. NADPH cytochrome p450 reductase takes an electron from nadph and reduces the p450 iron to a reduced state
6. the RH hydrogen is abstracted
7. a second electron either from p450 reductase or b5 reductatse gets added to the bound oxygen, reducing it into its activated form
8. one oxygen atom goes into water
9. ferric iron is regenerated

A

1, 5, 2, 7, 3, 8, 6, 4, 9

162
Q

which side does POR act

A

cytosolic

163
Q

what is the role of POR

A

reducing p450 so it can bind o2

164
Q

which are the major p450 families for xenobiotic metabolism

A

1-3

165
Q

what do p450 families 4-51 do

A

biosynthetic rxns, met of endo subs

166
Q

how did p450 genes evolve

A

duplication of og genes, accumulation of mutations

167
Q

how are p450s categorized

A

based on gene sequences

168
Q

CYP1A and CYP1B are in the same ____ but not the same ______. this means their amino acid identity is roughly _________ the same

A

family, subfamily, >40%

169
Q

the most dominant p450 is

A

cyp3a

170
Q

is abundance correlated with importance

A

no

171
Q

t/f: drug met is always protective

A

false

172
Q

main consequences of drug met:

A

stable metabolites (inactivating, pro drug activating, activity maintaining)

chemically reactive metabolites (covalent binding -> toxicity)

173
Q

example of drug inactivation

A

acetominophen to acet. sulfate via sulfonation or acet. gluc via glucoronidation

174
Q

example of pro drug activation

A

cyclophosphamide to phosphoramide mustard (active metabolite to kill cancer cells)

175
Q

example of stable metabolite formation

A

propafenone to 5 hydroxypropaenone (antiarrythmia)

176
Q

example of chemically reactive metabolite

A

anticonvulsants (phenytoin, carbamazepine, phenobarbital), form arene oxide, covalently bind, forein body, autoimmune response

177
Q

where does most drug biotrans take place

A

liver (but also happens almost everywhere

178
Q

when can tissue specific toxicity occur

A

when there is expression of certain enzymes in a tissue (even if the tissue has low drug met, there are some hotspots)

179
Q

how will first pass effect alter drug

A

drug gets activated or inactivated before reaching circ

180
Q

how do we biotranform so many drugs

A

enzyme multiplicity, broad substrate selectivity

181
Q

what do phase 1 rxns do

A

introduce new functional groups to the drug

182
Q

what do phase 2 rxns do

A

make the drug water soluble for excretion

183
Q

is it always phase 1 -> phase 2

A

no

184
Q

example of drug going through both phase 1 and 2

A

codeine to morphine via p450, morphine to m3g via ugt

185
Q

example of direct conjugation

A

morphine to m3g via ugt

186
Q

t/f: morpheine is only made from codeine

A

false, also made from heroin via phase 1 deacetylation

187
Q

phase 1 rxs

A

monooxygenation, oxidation, dehydrogenation, reduction, hydrolysis

188
Q

phase 2 conjugating enzymes

A

udp glucoronosyltrans
glutatthion s trans
sulfotrans
n-acetyltrans
methyl trans

PCL201 (19 decks)

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