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
|
|
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
|
|
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
|
|
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
|
|
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
|
|
Term
| If an individuald contained a wild-type allele of CYP2D6*1 or *2, you would you call them a _______ metabolizer |
|
Definition
|
|
Term
| What population is ~8% poor metabolizer with CYPD6*4, CYP2D6*5? |
|
Definition
|
|
Term
| What population is ~51% poor metabolizer with CYP2D6*10 (responsible for decreased neuroleptic and antidepressant metabolism) |
|
Definition
|
|
Term
| What population is ~17-24% poor metabolizer with CYP2D6*17? |
|
Definition
|
|
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
|
|
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
|
|
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
|
|
