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72 Cards in this Set

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  • Back
What are Xenobiotics?
Foreign chemicals that are of no use to the body; no help with Energy, catalysis, or structure.
Body must Eliminate Them
What 2 things can happen to Xenobiotics in the body?
1. Detoxification - gets rid of the toxin by metabolism
2. Activation to something worse -> an electrophile
Into what 3 stages is Drug Metabolism divided?
1. P450 reaction
2. Conjugation
3. Excretion
What are the 5 basic characteristics of Xenobiotics?
1. Low MW
2. Nonpolar
3. Hydrophobic/lipophilic
4. Easily cross plasma membranes
5. Poorly excreted
Where in cells does detoxification occur?
Smooth endoplasmic reticulum
What occurs in drug metabolism
-Phase 1?
-Phase 2?
1 = insertion of a polar group on the xenobiotic by P450

2 = conjugation of another molecule to the polar group
What 3 polar groups are inserted by P450 enzymes?
OH, SH, or NH2
3 Molecules conjugated to polar groups by Phase II enzymes:
-Glutathione GSH
-Sulfate SO4
How can P450 enzymes cause cancer?
By activating a xenobiotic instead of detoxifying it.
What is a common mutation cause by activated xenobiotics?
GC base pair mutation to TA
What is BenzoApyrene?
A weak carcinogen in cigarette smoke and coal -> but it turns into a strong carcinogen when activated by P450
What is the product when Cyp450 activates Benzo(a)pyrene?
a Highly reactive epoxide that nonenzymatically reacts with DNA
Why are P450 enzymes called that?
Because they exhibit max absorption at 450 in CO
What is the active group in P450 enzymes?
-Type of reaction
Heme - monooxygenases
-one O goes to water
-one O goes to xenobiotic
Where is the reactive group located on a Cytochrome P450?
Near the C-terminus in a heme binding pocket bound to a highly conserved CYSTEINE residue
What is bound to heme in P450 enzymes?
Top ligand: Cysteine

Bottom ligand: H2O
How are P450 enzymes activated?
By replacing H2O with O2
What tissues have especially high amounts of P450 enzymes?
-Intestinal mucosa
What enzyme is needed to keep P450 enzymes active?
NADPH CYP450 Reductase
Requirements of NADPH Reductase:
-FAD/FMN (Riboflavin)
What is the flow of electrons in the P450 chain of things?
2. FAD
3. FMN
4. Heme Fe3+ -> Fe2+
What 3 groups can be conjugated to the polar group inserted on a xenobiotic during metabolism?
2. GSH
3. SO4
What is the most common type of conjugation? What enzyme does it?
UDPGA - UDPGA Transferase
What is the source of UDPGA for this reaction?
Uridine diphosphate-glucuronic acid - a nucleotide
What tissue is GSH-S-Transferase especially high in?
Liver - has high concentrations of both GSH and the enzyme.
What enzyme catalyzes the UDPG transfer, and where is it found?
UDPG-transferase, in ER membrane in hepatocytes -> liver!
What 2 molecules are especially acted on by GDPGTransferase?
-Steroid hormones
What enzyme transfers GSH to xenobiotics?
Glutathione S-Transferase
Where is GSH-S-Transferase especially found?
In the liver - it accounts for about 10% of soluble proteins in the liver.
What reaction occurs in the transfer of GSH to xenobiotic?
GSH is added to ANY very electrophilic Epoxide converting it to a hydroxyl group.
Why is GSH biologically important?
Because it neutralizes the highly reactive epoxides that can be formed by P450 enzymes.
What is induction?
increased transcription and concentration of a P450 in response to the presence of a xenobiotic.
-Muscle relaxant
-Normal T1/2 = 3 hrs
Drug interactions with Zoxazolamine:
-Phenobarbital makes T1/2 = 1 hr
-Benzoapyrene makes T1/2 = 15 min
Drug interactions with Coumadin:
Phenobarbital greatly reduces the T1/2; if taken at same time and Phenobarb discontinued, have to reduce levels of Coumadin too.
P450 for birth control pill:
What induces CYP 3A4, what is result?
-St. John's Wort

Result: unplanned pregnancy
-Product of pulp and paper mills
-Element in Agent Orange herbicide
Mechanism of Dioxin
Analagous to steroid hormones - lipophilic protein diffuses into cell, binds receptor, induces conformational change that allows binding to XRE
What is XRE
Xenobiotic response element
XREs act as:
Transcriptional enhancers
What is the protein structure of the receptor for dioxin?
Helix-loop-helix (binding causes dimerization and binding to DNA for transcription)
Result of Dioxin/AH receptor binding XRE?
Transcription of Dioxin Metabolism Phase I/II enzymes
Why is Dioxin toxic?
It competes with the normal ligand for the Ah receptor and gets converted to an even more toxic compound that damages DNA
CYP for:
-Birth control
CYP 1A1 - dioxin
CYP 2E1 - aspirin
CYP 3A4 - birth control
Normal Tylenol metabolism:
3 routes:
1. UDPG transfer (50%)
2. S-Transferase (PAPS) 20-40%
3. CYP2E1 (10%)
How can Phase II enzymes just act on tylenol?
It is acetominophen - it has hydroxyl groups already.
What is the product of the CYP2E1 pathway?
NAPQ1 - very hepatotoxic but not produced in very high amts normally.
What causes increased toxicity of APAP (acetominophen)?
When you overdose
What normally happens to NAPQ1?
Conjugation with GSH; when too much is ingested, GSH levels are exhausted and more NAPQ1 results
2 things that enhance acetominophen hepatotoxicity:
1. Fasting
2. Chronic Alcohol - induces CYP2E1!!
3. Overdosing on it
What are 3 thoughts on how P450 levels are Repressed?
1. Mechanism based
2. Disease states
3. Multiple drug therapy
What is the Mechanism-Based Inhibition theory about P450 repression?
Parent drug is not inhibitry, but 1 cycle of Phase I metabolism activates the drug so it irreversibly binds the P450.
We saw chronic alcohol use upregulate CYP2E1, but how can it also affect P450 levels?
Cirrhosis decreases expression of some P450s
What is an example of Multiple drug therapy repressing P450s involving Dicumarol?
Taking Dicumorol represses the P450 for Phenytoin and Tolbutamide -> they stay around longer.
Why does Dicumarol affect metabolism of Phenytoin and Tolbutamide?
B/c they all compete for the same cyp 450
What medications are very bad to take with Erythromycin?
Verapamil / Diltiazem - blood pressure medicines
Why is it bad to take Erythromycin and Verapamil or Diltiazem at the same time?
Erythromycin represses P450s that metabolize BP meds -> results in cardiac arrythmia and increases risk of cardiac death 5 times!!
Effect of taking Grapefruit juice:
-Inhibits CYP3A4
-Metabolizes approx 50% of prescription drugs
What is the adverse effect of Grapefruit juice?
It inhibits CYP3A4 which is necessary for clearing many cardiovascular drugs (statins) Result: too high levels
What is a positive effect of drinking Grapefruit juice?
Activates aflatoxin B1 which protects against hepatic cancer.
What are cruciferous veggies?
Brussel sprouts
What is the effect of eating cauliflower?
Induces CYP1A1 (dioxin) which reduces carcinogenic Aromatic hydrocarbins in circulation.
What dietary deficiency can cause P450 Repression? How?
Riboflavin B2 deficiency - no FAD/FMN - no NADPH reductase
What genetic factor influences P450 expression?
Polymorphism - some people just have different levels and isoforms of P450s
What was the first P450 polymorphism discovered?
CYP2D6 Deficiency
What is CYP2D6 needed for?
Hydroxylating Debrisoquine (antihypertension drug)
What are the 2 phenotypes associated with CYP2D6 polymorphism?
-Poor metabolizer (low excretn)

-Extensive metabolizer (normal)
How is CYP2D6 deficiency detected?
Only in a drug challenge:
-Administer dextromethorphan
-Measure O-demethylated metabolite excreted
What other drug is CYP2D6 essential for?
Codeine - CYP2D6 activates it to morphine in order to do its analgesic thing.
Why do we care about CYP2D6 deficiency?
B/c it is undetected until drug challenge; don't want to give a drug that won't be adequetely metabolized and kill the pt!
What drug is an inhibitor of CYP2D6?
Prozac; so give lower amts of drugs metabolized by CYP2D6 if you're also prescribing Prozac.