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CXPT 610 > Lecture 5/6: Types of CYP Phase I Mediated Metabolism > Flashcards

Lecture 5/6: Types of CYP Phase I Mediated Metabolism Flashcards

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1
Q

What are some heme proteins?

A

cyp450
hemoglobin
myoglobin

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2
Q

Why are cyp450 considered heme proteins?

A

because they have an iron in the porphyrin ring giving its color

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3
Q

What are the type of reactions that cyp mediates?

A

a diverse reaction with organic substrates

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4
Q

What are the substrates for cyp?

A

they include endogenous substrates including steroid hormones and lipids

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5
Q

Where are CYPs mainly expressed?

A

all tissues but mainly the liver and intestine and found in the smooth er

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6
Q

Why do enzymes need metal?

A

to bidn the oxygen and undergo the electron transition - heme group is hb with iron - the iron captures electrons which is why all enzymes need calcium or iron De2+

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7
Q

What occurs with cancers and ferroptosis?

A

iron in tissues goes from 2+ to 3+ in the mitochondria

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8
Q

Where is iron located in the cell?

A

ER and mitochondria

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9
Q

What types of cells is cancer tissue made up of?

A

cancer cells and normal cells so need to see how they interact with each other

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10
Q

What are some types of oxidative reactions done by microsomal enzymes?

A

aromatic hydroxylation
epoxidation
aliphatic hydroxylation
n-dealkylation
n-oxidation or n-hydroxylation
o-dealkylation
s-dealkylation
s-oxidation or sulfoxidation
desulfuration
oxidative dehalogenation

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11
Q

What are some types of oxidative reactions done by non-microsomal enzymes?

A

alcohol oxidation
aldehyde oxidation
amine oxidation or oxidative deamination
monoamine oxidation
diamine oxidation
purine oxidation

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12
Q

Why do stem cells have a high aldehyde dehydrogenase?

A

to make cooh

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13
Q

In aromatic hydroxylation what is the position of the OH group relative to the R group?

A

mostly para (can get meta as well)

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14
Q

What amino acids make GABA, serotonin, and catecholamines?

A

GABA - glutamate
serotonin - tryptophan
tyrosine - all catecholamines
-proteins make endogenous signals to keep us healthy deamination makes these NTs from amino acids

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15
Q

What reactions are included in cyp450 mediated metabolism?

A

oxidation, reduction, hydrolysis, and hydration, and isomerization

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16
Q

What is the main function of phase i metabolism?

A

to prepapre a compound for phase ii metabolism or elimination

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17
Q

What do mixed function enzyme systems found in microsomes of many cells especially the liver kidney lung and intestine do?

A

perform many different functionalization reactions

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18
Q

As you age why does conjugation change?

A

due to less hormones

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19
Q

Complete the equation: NADPH H+ + O2 + Drug —>

A

NADP+ + H2O + Oxidized Drug

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20
Q

What binds to a reduced heme Fe(Ii) and absorbs at 450nm?

A

carbon monoxide

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21
Q

The cyp monooxygenase family is a major catalyst of what?

A

drugs and endogenous compound oxidations in the liver, kidney, gi tract, skin and lungs

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22
Q

What do oxidative reactions require?

A

the cyp heme protein the reductase nadph phosphatidylcholine and oxygen

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23
Q

Where are cyps located and what are they found in close association with?

A

the smooth er
-in close association with nadph-cyp reductase in 10/1 ratio

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24
Q

Why is iron Iv really reactive?

A

cause it is sterically hindered

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25
Where do electrons go in phase 1 metabolism?
-electrons go from NADPH H+ to FAD and then iron cyp450 heme and then oxygen and form water and the oxidized drug
26
Why is cyp found in the body?
-hydrophobic molecules have double bonds which can be oxidized to becoming reactive molecules -lipids and steroids are hydrophobic molecules where metabolism is required to convert them into bioactive molecules
27
Wgat are the types of chemical reactions found in metabolism?
phase i - increase polarity or hydrophilicity of compounds found in the body phase ii - conjugation with endogenous molecules to neutralize the phase i mediated molecules
28
What are some hydrolysis phase i metabolism reactions?
hydrolysis of amide and its derivatives -ester hydrolysis -Due to many esters in body by carboxylesterases - I.e. cAMP - phosphodiesterase is broken down and is a controlled metabolic secondary messenger - lots of esterase get into cell then compete with phosphodiesterase so we need to get rid of exogenous esterase
29
What are some hydroxylation phase i metabolism reactions?
R-H + O2 + NADPH + H+ ----> R-OH + NADP+ + H2O aromatic hydroxylation - para is preferred aliphatic hydroxylation - Hydrogens are equally susceptible to hydroxylation - this process is how we metabolize fatty acids - then the hydroxyl can turn into aldehyde
30
What occurs in deamination?
an amine becomes a ketone or aldehyde
31
What happens in o-dealkylation?
and ether loses its alkyl group and becomes a hydroxyl
32
What happens in n dealkylation?
a secondary or tertiary amine loses its alkyl group and becomes a primary or secondary amine and forms an aldehyde
33
What happens in n oxidation?
an OH group is added to an amine makes R3N+O-
34
What happens in sulfoxiation?
a thioether gets an OH group added which then oxidizes to make a sulfoxide
35
What happens in double bond oxidation?
make an epoxide - very reactive cause steric hindrance - a hydroxyl group can intercalate on a double bond
36
What are some oxidative reactions?
carbon hydroxylation heteroatom hydroxylation heteroatom release rearrangement related to heteroatom oxidations -oxidation of pi system -hypervalent oxygen sustrate
37
What are some reductive reactions?
CCl4 ---> Cl- + CCl3. --(O2)----> CCl3O2.-----> CCl2O + Cl+
38
What are some drugs that inhibit cyp3a4
macrolide antibiotics - erythromycin clarithromycin antifungal agents - ketoconazole itraconazole other agents hiv protease inhibitors - keep drugs in the body forever
39
How is terfenadine converted to fexofenadine?
-terfenadine is a non sedating antihistamine that was marketed under the brand name seldane -the drug is metabolized by cyp3a4 -after marketing clinicans used seldane and erthromycin together to treat upper respiratory functions -patients died of cardio causes -the combo seldane with eryhtromycin led to accumulation of terfenadine which caused qt prolongation leading to torsade de pointe -Terfenadine hangs around when you give erythromyocin and hangs around and is lipophillic and can change membrane potential by implanting in it and changing the QT prolongation wave by making it wider - heart pumps slower - less blood circulation. And clot - do this with very young people to prevent heart diseases if phase 1b ddi study
40
What can intrinsic clearance be measured in?
HLM and scaled to predict the hepatic in vivo clearance in humans
41
What can be used to identify DMEs?
the effect of co-incubated cyp selective chemical or monoclonal antibody inhibitors on rate of metabolism in HLM can be used to identify primary dmes
42
What can incubation with recombinant cyps be scaled to?
predict in vivo clearance using RAFs or relatuve atcivity factors and or relatuve hepatic abundance of enzymes
43
How can a correlation of rate of metabolism be made?
with a panel of HLM donors with an n greater than or equal to 10 that have been phenotype for the major dmes
44
What happens in aliphatic oxidation?
an alkane gets oxidized to an alcohol
45
What happens in aromatic hydroxylation?
an aromatic ring becomes an arene oxide or epoxide and then this make a para substituted aromatic ring with a hydroxyl group
46
What happens in N-dealkylation?
you have a secondary amine group and you ass an OH onto the methyl group attached to the amine and then you get an aldehyde and a primary amine
47
What happens in o delakylation?
yiu have an ether and add an Oh onto the methyl of th ether and then get a primary alcohol and an aldehyde
48
What happens in s-demethylation?
You have R-S-CH3 and then get an OH on the methyl group and then get a primary thiol and an aldehyde
49
What happens in oxidative deamination?
you have a tertiary C with an amine group attached to it - get an OH attached to it as well and then for a ketone and the amine group leaves
50
What happens in sulfoxide formation?
you have an R-S-R and then you attah an OH group to the S and then get R=S=O-R aka sulfoxide -why do we have drugs that are not sulfa based - acetaminophen toxicity - sulfur smells bad and drink it cause liquid and very reactive metabolite
51
What happens in N oxidation?
have a tertiary amine and then add an Oh group to the N and then get R3N=O
52
What happens in N-hydroxylation?
have a secondary amine and then add an OH group to the N
53
If you have a methyl group on an arimatic ring what can you do to increase the exposure in the blood and increase potency?
swap the Hs for Fs -chlorine is not as strong and bromine is too big -has greater interactions with the binding pocket if you change to fluorine due to more electrons cause nonpolar
54
If a drug is nucleoside based why can females process it better than males?
It is a nucleoside or nuclei base and females can import it better than men so they have mechanism to import nucleosome better cause women have up regulation of nucleoside transporters so get more toxicity but more efficacy cause women can have babies - need to look at intracellular accumulation
55
The N hydroxylation of AAF is the first step in what?
towards the development of carcinogenic agent aflatoxin made in moldy food and in peanuts and is deadly and is metabolized by cyp4501a2 which is n acetyl transferase and makes this a carcinogen
56
What happens in oxidative dehalogenation?
R-C(X)-H2 + O2 ----> R-C(X)(H)-OH ----> R-C=O-H + HX
57
What happens in desulfuration?
a sulfoxide attached to a C or P become a =O instead
58
What does the final product of phase i metabolism usually include?
OH, NH2, SH, COOH
59
What can the functional group added by phase i metabolism be acted upon by?
phase ii conjugative enzymes -the main function of phase i is to prepare the compound for phase ii metabolism not excretion
60
In what tissues are some cyps enzymes located?
1a1 - lung, kidney, gi tract, skin, placenta, and etc 1b1 - skin, kidney, prostate, mammary 2a6 - lung nasak membrane 2b6 - gi tract lung 2c - gi tract, small intestinal mucosa, larynx, and lungs 2e1 - lung, placenta 2f1 - lung, placenta 2j2 - gi tract , lung placenta, fetus, uterus, kidney 4b1 - lung, placenta 4a11 - kidney
61
What is monoamine oxidase?
mao, mitochondrial - oxidatively deaminates endogenous substrates including NTs dopamine serotonin, norepinephrine, epinephrine, drugs include triptans
62
What do alcohol and aldehyde dehydrogenase do?
they are non specific enzymes liver cytosol and they are in charge of ethanol metabolism
63
What does xanthine oxidase do?
converts bypoxanthine to xanthine and then to uric acid -drugs include theophylline, 6-mercpatupurine - allopurinol is a substrate and inhibitor of xanthine oxidase - Breaks down DNA to uric acid and then get gall stones for xanthine oxidase
64
What does flavin monooxygenases do?
fmos - are membrane bound and nadph dependent - catalyze the oxygenayion of mitrogen, phopshorus, sulfur, particulalry facile formation of n-oxides - cimetidines
65
What are some other non cyp oxidation drug metabolizing enzymes?
o-meyhylation, s methylation, amino acid conjugation glycine taurine glutathione, metaboliotes or functional groups offer clues as to what enzyme is involved -esterases, amidases, n-acteylation
66
What are some non cyp biotransformations?
oxidations hydrolyses conjugation - phase ii reactions major conjugation reactions -glucuronidation - high capacity -sulfation - low capacity -acetylation - variable capacity -procainamide, isoniazid
67
What are some other conjugation reactions?
o-methylation, s-methylation, amino acid conjugation (glycine, taurine, glutathione) -many conjugation enzymes have polymorphisms
68
What is lidocaine good for?
-lidocaine is good for arrhythmias and is tachycardia and put this local anesthetic slow the firing - lidocaine is used for heart then but now for epidurals and they do work and - have very fast half life of lidocaine which is why it is infused
69
What is first pass metabolism?
following nonparenteral administration o a drug a significant portion of the dose may be metabolically inactivated in either the intestinal endothelium or the liver before it reaches systemic circulation -this limits the oral availability of highly metabolized drugs
70
What is nitroreduction?
RNO2---> RNH2 -found in microsomes and cytosol
71
What is azo reduction?
RN=NR' -------> RNH2 + R'NH2
72
What is alcohol dehydrogenation?
-take an OH group and make it H and convert NADH + H+ ----> NAD+ + H2O
73
What is dihydropyrimidine dehydrogenase?
5-FU ---(DPYD)----> 5f,5,6,-dihydrouracil -inactivated 5fu by ring reduction -can get 5fu toxicity if have deficiency in enzyme -can detect enzyme deficiency through a molecular assay of wbcs
74
What is amide hydrolysis?
take an amide and make it cooh and amine
75
What is ester hydrolysis?
take an ester and make it cooh and an alcohol
76
What is epoxide hydrolase?
-takes an epoxide and makes it two OH groups
77

CXPT 610 (8 decks)

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