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Fundies test 4
12/3 Drug metabolism
46
Dentistry
Graduate
12/06/2013

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Term
**What are the functions of Drug Metabolism?
Definition
1. Decrease biologic activity of drugs and xenobiotics (anything foreign).

2. Increase excretion by metabolism to water-soluble
metabolites.

3. Metabolize prodrug to active drug. Also convert
active drug to different active drug.

4. Generate toxic or carcinogenic metabolites.
Term
What are ways that the body excretes drug metabolites?
Definition
Many metabolites are charged (become ionic), water soluble
Glucuronides and sulfates have pKa’s of 1 - 2 (makes them water-soluble)
Anion and cation transport systems in kidney (to excrete in urine)
Efficient removal of charged metabolites from plasma
Excretion from liver into bile and GI tract
Term
When Diazepam (tranquilizer) is demthylated/hydroxylated in the body, it turns into?

When Imipramine (serotonin uptake blocker) is demethylated, it turns into?
Definition
Oxazepam (anti-convulsant)

Desmethylimipramine (Norepinephrine uptake blocker)
Term
An example of a prodrug conversion is?
It undergoes Azo-reduction to become?
Definition
Prontosil

Sulfanilamide (antibiotic)-competes with p-aminobenzoic acid
for conversion to folic acid
Term
Identify the following reactions as Phase I or Phase II

Oxidation
Glucuronidation
Sulfation
Reduction
Hydrolysis
Acetylation
Hydration
Methylation
Isomerization
Dethioacetylation
Glutathione conjugation
Amino acid conjugation
Fatty acid conjugation
Definition
Oxidation-I
Glucuronidation-II
Sulfation-II
Reduction-I
Hydrolysis-I
Acetylation-II
Hydration-I
Methylation-II
Isomerization-I
Dethioacetylation-I
Glutathione conjugation-II
Amino acid conjugation-II
Fatty acid conjugation-II
Term
Which phase reaction are conjugation reactions?

Which phase reaction slightly modify chemistry of a compound. May have large effects on activity, properties and toxicity?
Definition
Phase II

Phase I (prepare compounds for Phase 2)
Term
What are highly charged, water-soluble and rapidly excreted compounds?
Definition
conjugates
Term
What is the family of heme containing mono-oxygenases, most powerful in vivo oxidizing system known. Found in ALL plant and animal families and evolutionarily very old. Causes a wide variety of reactions a given compound can undergo (multiple pathways)?

Is this a phase I or II reaction?
Definition
Cytochromes P450

Phase I
Term
What are the 2 types of mixed function oxidase systems of P450 found in the body?
Definition
Liver Microsomal Mixed Function Oxidase System (classic, found in ALL cells except muscles and RBCs)

Adrenal Mitochondrial Mixed Function Oxidase System
Term
What are the 2 components of the Liver Microsomal Mixed Function Oxidase System and what do they do?
Definition
NADPH Cytochrome P450 Reductase (one enzyme transfers electron from NADPH to CYP450 with the help of FAD and FMN)

Cytochromes P450 (inserts oxygen atom=monooxygenase)
Term
True or false: the liver microsomal MFO system is found in ALL animal phyla and ALL human tissues.
Definition
False.

Found in all animal phyla.
Found in all human tissues EXCEPT skeletal muscle and red blood cells (it's a heme containing protein so don't want it to be competing in the blood and muscle for oxygen binding)
Term
Which NADPH Cytochome P450 Mixed Function Oxidase System is involved in steroid biosynthesis?
Definition
Adrenal Mitochondrial MFO System
Term
In the Adrenal Mitochondrial MFO System, what replaces NADPH CYP450 reductase (transfers electron from NADPH to CYP450)?
Definition
Adrenodoxin reductase & adrenodoxin
Term
In the Mixed Function Oxidase Reaction, the _______ takes electrons from _______ (one at a time) and transfers them to ______ (embedded in the plasma membrane). Then it binds a _______ and ______.

What are the end products?
Definition
REDUCTASE takes electrons from 2NADPH and transfers them to CYP450. Then it (reductase) binds to a SUBSTRATE and molecular OXYGEN

transfers one oxygen to the substrate as a hydroxyl group, and the other oxygen then ends up as water (monooxygenase reaction)
Term
What is one of the most important CYP450 reaction that allows for future conjugation and what are the 3 types?
Definition
CYP450 Hydroxylation Reactions Aromatic Ring Hydroxylation Aliphatic Ring Hydroxylation Aliphatic Hydroxylation
Term
What is an important Cytochrome P450 reaction that adds an oxygen across a double bond in a conjugated ring system which can cause the compound to be very electrophilic (toxicity)
Definition
Epoxidation (all epoxides are reactive/toxic)
Term
What is an important Cytochrome P450 reaction that involves the insertion of a hydroxyl group and then rearrangement (double bond to oxygen and loss of NH3)?
Definition
Oxidative deamination
Term
When you eat something, it has color because it has ______ (absorbs light). It is (hydrophobic or hydrophilic) and you must _________ to get rid of it.
Definition
ring structure
metabolize
Term
**What is the major, most important enzyme CYP450 isoform found in the liver for drug metabolism (~50%)?

Which is the other isoform (~30% drug metabolism)?
Definition
CYP3A4

CYP2D6
Term
If an individuald contained a wild-type allele of CYP2D6*1 or *2, you would you call them a _______ metabolizer
Definition
Rapid metabolizer
Term
What population is ~8% poor metabolizer with CYPD6*4, CYP2D6*5?
Definition
Caucasian
Term
What population is ~51% poor metabolizer with CYP2D6*10 (responsible for decreased neuroleptic and antidepressant metabolism)
Definition
Chinese
Term
What population is ~17-24% poor metabolizer with CYP2D6*17?
Definition
Black
Term
If an individual had high rates of metabolisms due to gene duplication of wild type genes, you would call them an ________ metabolizer.
Definition
ultrarapid metabolizer (doesn't respond to drug)
Term
Is codeine or morphine a good opiate?
What demethylates it?
Definition
Morphine is a good opiate (codeine is poor)

codeine (analgesic prodrug) demethylated to morphine by CYP2D6
(CYP2D6 Poor metabolizers have little to no analgesic effect and have low risk of codeine dependence)
Term
what is the number of forms of Flavin-containing Monooxygenases are there in human tissues?

Which is the predominant form?

Can they be regulated independently of each other?
Definition
5

FMO3

yes, they are separate gene products so they can be regulated independently of each other
Term
Flavin-containing Monooxygenases have covalent bound _____ and require ________.

They are capable of oxidizing ____________ and do not react with _______ charged compounds.

They catalyzes some of the same reactions as the ____ system
Definition
FAD moiety and require NADPH and O2 (like P450)

Capable of oxidizing nucleophilic heteroatoms (O, N, P). Do not react with negatively charged compounds

Catalyzes some of the same reactions as the MFO system
Term
What do individuals lack if they have fish-odor syndrome?

Compound is the cause of this?
Definition
FMO3

Cysteamine is produced in the body and is metabolized to trimethylamine, which is usually metabolized by FMO3, but if it is not present, you will be left with trimethylamine, which gives the fish smell.
Term
What are the reactions of the FMO system?
Definition
mainly nitrogen, sulfur, and phosphorous oxidations (like P450)
Term
What enzyme add water to epoxides to create a dihydrodiol?
Definition
epoxide hydrolases (protects us from toxic properties of oxirane rings)
Term
What is the cofactor in glucouronidation?
What is the acceptor compound called?
Is this a phase I or II reaction?
Definition
UDP-glucuronic acid
aglycones
phase II
Term
What may the glucoronic acid moiety be linked to?
What does it always form?
Definition
O,N,S,C atoms (why it's so abundant=broad substrate specificity)

always form beta-D-glucuronides
Term
Why are the conjugates charged at physiological pHs in glucuronidation?
Definition
pKa of glucuronic acid is 2 so the conjugates are charged at physiological pHs.
Term
____________ consist of a superfamily of enzymes with 2 families of related enzymes in glucuronidation.
Definition
UDP-glucuronosyltransferases (UGTs)
Term
What reaction transfers a sulfonate group (SO3) to produce a sulfate using PAPS?

Is this a phase I or II reaction?
Definition
sulfotransferase reaction

Phase II
Term
If 2-Napthylamine (aromatic amine=carcinogen) undergoes oxidation by MFO and then sulfated, will it become non-carcinogenic and excreted or become a carcinogen that can bind to DNA?

If it undergoes the sulfonate reaction through P-PST (PAPS) will it be non-carcinogenic or carcinogenic?
Definition
carcinogen

non-carginogen

(end products depend on enzyme composition of tissues)
Term
When p-Aminophenol is acetylated, what does it become?

When sulfanilamide is acetylated, what does it becomes?
Definition
acetaminophen (acetylCoA donates CoA)

N-Acetylsulfanilamide
Term
What reaction uses S-adenosylmethionine (SAM) as a cofactor, and does NOT change the charge of the compound (may reduce solubility)?

Is this phase I or phase II reaction?
Definition
Methylation reaction

phase II
Term
What conjugation reaction is unique in that it acts as nucleophile to bind electrophiles (ex. epoxides) which provides an important protective function?
Definition
Glutathione conjugation
Term
Glutathione is a tripeptide consisting of?
Where does all the important chemistry occur?
Definition
Glutathione (GSH) is a tripeptide consisting of GLU, CYS & GLY. The GLU is linked to CYS via the gamma-carboxy group.

All the important chemistry occurs at the thiol group of CYS.
Term
Glutathione can react spontaneously with electrophilic compounds or its rate of reaction and specificity can be increased by a family of _______________
Definition
glutathione S-transferases (GSTs)
Term
Glutathione conjugates may be further metabolized to CYS conjugates and mercapturates (N-acetyl-CYS) conjugates in the ______.
Definition
kidney
Term
The level of activity of __________ in the kidneys is extremely variable
Definition
N-acetyltransferase (add an acetyle group to the cysteine to form mercapturate)
Term
When there is an increase dose of acetaminophen, there is a (increase or decrease) in glutathione levels
Definition
decrease

(caused by covalent binding of acetaminophen to proteins in the liver-->hepatocellular necrosis when too much acetaminophen)
Term
What is the basic destruction of P450 with a drug (binds to P450 and destroys it so anything P450 metabolizes increases)?
Definition
suicide inhibition (pseudo-suicide-slightly different mechanism-intermediate reacts)
Term
What is the adaptive increase in the number of
molecules of a specific enzyme secondary to increased
Synthesis or decreased degradation of that enzyme (body adapts to what it needs)?
Definition
Enzyme induction
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