Dietz Flashcards
Phase I metabolism is usually catalyzed by what enzyme?
CYP450
T/F Your metabolite gets higher water solubility (become more hydrophilic) after amino acid conjugation.
F
Glucuronidation formula
R-OH + sugar –> R-O-sugar
Sulfate conjugation formula
ROH + SO4 (-2) —–> R-O-SO3-
Glutathione conjugation formula
RX + GSH —> R-S-G
Glucuronidation substrates
Phenols, 1 alcohol, 2 alcohol, 3 alcohol, aromatic amines, acids
Sulfate conjucation substrates
Phenols, alcohols, aromatic amines
Is GSH nucleophile or electrophile?
Nucleophile. Becomes GS- and helps get rid of electrophiles
Most conjucation of glucuronidation are active or inactive? What’s an exception?
Most are inactive except for morphine-6-glucuronide
Reactions of glucuronic conjugation? What does it conjugate with?
Bilirubin, drugs, pesticides, carcinogens
What kind of conjugation does Zileuton have? And what does it form?
UTG conjugation (glucuronidation) and it’ll form N-O-glucuronide
What’s the Crigler-Najjar syndrome?
Jaundice. Mutated UGT1A1 resulting in the inability for the UGT to perform glucuronidation. A bunch of unconjugated bilirubin left, causing toxicity.
What’s Gilbert’s syndrome?
When the UGT1A1 enzyme is off resulting in UGT not able to glucuronize bilirubin causing an excess of it in the body, thus jaundice.
What’s Gray Baby syndrome?
When neonates don’t have enough UGT yet and fails to conjugate chloramphenicol, leading to vasomotor collapse and cell toxicity.
What is UGT1A1*28? What does it cause?
It’s a varient that causes less expression of UGT1A1, leading to unconjugated hyperbilirubinemia and decreased drug clearance leading to toxicity ex. irinotecan
What can lead to too much SN38?
When there’s a lack of expression of UGT1A1 and the SN38 (which came from prodrug irinotecan) can’t be conjugated into an inactive form and will just keep accumulating.
Why do some glucuronides have long half lives?
Some may re-enter the intestine and reabsorbed again, deconjugated by B-glucuronidase in the colon, making the half life longer.
What’s PAPS? Is it an electrophile or nucleophile?
Co-factor for sulfate conjugation. Electrophile.
What are sulfate conjugation substrates?
Phenols (most common), alcohols, aromatic amines, N-hydroxls
How does metabolism through sulfate conjugation alter rate of renal clearance of a drug?
It makes the drug a lot more hydrophilic and water soluble by adding that SO3-
What is Phenacitin? How excreted?
Pain/fever reliever. Can be excreted through sulfate conjugation.
How to get estrogenic activity?
By having enzyme sulfatase remove the sulfate on the conjugated estrogen and make it active again.
How is DMBA activated?
DMBA will go through sulfate conjugation and after that the sulfate group will leave through SN1, making the DMBA a carbocation, which is super reactive and can cause carcinogen. It can be detoxified by GSH.
What does glutathione conjugation try to do? (eliminate what?) And what groups does it target? Name 4.
Gets rid of electrophiles
Epoxides, alkyl halides, AB-unsaturated carbonyls quinones
What’s a Michael receptor?
It’s an AB-unsaturated carbonyl and is an electrophile which can be attacked by the nucelophile GSH.
Explain Aflatoxin detoxification.
Basically aflatoxin can become a toxic bitch by forming an epoxide after being metabolized by P450. Then GSH comes in like a mofo hero ass (with the help of GST) and attack the shiz outta that electrophile and walla DETOX.
Name a drug that can go through N-acetyltransferase and name the co-factor that it needs
Procainamide, it needs acetyl-CoA
What are NAT1 and NAT2? And where are they located?
They are 2 forms of N-acetyltransferases. NAT1 is in the urothelium and colon epithelial cells and NAT2 in the liver and intestine (more important one)
N-acetyltransferase (does/does not) make the metabolite of Procainamide water soluble
does not, thus more needs to be done for it to be eliminated
How to form the really dangerous acetyl radical?
First have the isoniazid go through N-acetyltransferase (NAT2)/acetyl CoA and get the N. Then it’ll be hydrolysed into isonicotinic acid and acetylhydrazine. The acetylhydrazine is the one that when metabolized by p450 would make scary af acetyl radical leading to liver toxicity.
What happens when you’re a super fast acylater?
You could get liver toxicity by making that acetyl radical
What happens when you’re a super slow aceylator?
You get accumulation of that isoniazid
How to make mercapturic acid?
After glutithione conj you cleave the glutamine and blycine and then it goes through N-acetyltransferase/acetyl CoA and you get the mercapturic acid which can be excreted in urine
Major metabolite of acetaminophen
Glucuronide, duhhhhh the most common type of metabolism
Explain how acetabminophen overdose can lead to liver toxicity
Acetaminophen can go through GSH (glutathione conj) but when GSH runs out, this protein would attack (attach itself) to acetaminophen metabolite and create protein alkylation which is toxic. But this is rare. Only 2% of acetaminophen will form the quinone imine.
Top 2 causes of human cancer death
Diet and tobacco
Major reason of drug attrition
safety and toxicology
What’s the whole Fen-Phen deal?
FEN-PHEN - Fenfluramine (Pondimin) + Phentermine (1959) DEXFEN-PHEN - Dexfenfluramine (Redux) + phentermine
30% patients abnormal echocardiograms with fenfluramine and dexfenfluramine
Name a COX 2 inhibitor drug. Why was it better than COX 1? Why is it not good now?
Vioxx approved for pain relief. Better than COX 1 cuz it caused less GI problems. But it was later found that it caused cardiovascular problems.
What is DES (diethylstilbestrol) and what was its problem?
Used to prevent miscarriage. Ended up being a teratogen which caused cervical cancer in daughters and reproductive abnormalities in sons.
What’s Thalidomide?
Used to be used as sleep aid and morning sickness from pregnancy, but now it causes serve birth defect like missing limbs. Approved to treat leprosy and multiple milenoma.
Three major mechanisms by which reactive intermediates produce toxicity
- Covalent binding to DNA, enzymes, etc.
- Noncovalent interactions by mechanisms such as formation of reactive oxygen species.
- Formation of protein covalent adducts leads to immunologically mediated toxicity (like skin rashes).
Which transferases have polymorphism?
NAT1 and NAT2, slow and fast acetylators
Slow acetylators of NAT2 will (get rid of/accumulate) isoniazid and cause __________.
Accumulate; neuropathy
Fast acetylators of NAT2 will (get rid of/accumulate) isoniazid and cause _____________.
get rid of; the formation of the scary af acetyl radical which will cause liver toxicity/hepatic damage
Alcohol induces _____ which enhances acetaminophen to cause liver toxicity
CYP450 2E1
Acetaminophen metabolites: Around \_\_\_\_\_% sulfate Around \_\_% glucuronide. Around \_\_% quinone imine Glutathione-acetaminophen
Around 20-40% sulfate
Around 40% glucuronide.
Around 2% quinone imine
Glutathione-acetaminophen
The more reactive the electrophile the ________ selective it is
Less
What is mechlorethamine (nitrogen mustards) an example of? And what does it do?
Direct acting genotoxic carcinogen. It doesn’t require bioactivation by P450. It’s a DNA alkylator, which means DNA as a nucleophile will attack it and be atached to it.
Second alkylation by mecholrethamine (nitrogen mustards) forms what and what does it signal?
It forms interstrand cross links and will signal apoptosis
What can sulfamethoxazole cause?
It can cause hypersensitivity to skin with by acting as an antigen.
Name the 3 types of reactive intermediates
- Electrophiles
- Free radicals
- Nucleophiles
Name 3 positively charged electrophiles (know wtf they look like)
- nitrenium ion
- carbocation
- aziridinium ion
Name neutral electrophiles
epoxide, arene oxide, quinone, quinone imine, quinone methide, alkyl halide, acyl halide
out of all the electrophiles which one is the most reactive and which is the least reactive?
Most: carbocation
Least: quinoids
___ % of metabolites are toxic
7%
Major toxic metabolite of drug is the _______ of ______ to _________.
Oxidation of phenols to quinones
What is Oltipraz and what does it do?
Oltipraz is a chemoprotection compound. It prevents Aflatoxin B1 from getting an epoxide by inhibiting P4501A2.
Name all the stuff that can form epoxides
Aflatoxin, Pulegone, Benzo[a]pyrene, Dichloroethylene
Dichloroethylene can create something toxic. What is it and which enzyme does it use?
It can form an epoxide metabolite through P4502E1
How is Safrole toxic?
It’s carcinogenic and hepatoxic by making a carbocation
What is Aristolochic acid and how is it carcinogenic? (what electrophile does it become)
It’s part of a plant and can cause permanent kidney damage. It can form a nitrenium ion.
How can Phenytoin cause toxicity?
Forming quinones and superoxide radicals
What makes quinones?
P450
How can Tamoxifen become toxic?
Forming quinoids or carbocations
What’s a drug that is very effective in treatment of small-cell lung and testicular cancer? What does it inhibit and what are the side effects?
The drug is Etopside. It inhibits topoisomerase and inhibit tumor cell replication. However the side effect is it can form quinones.
What is Diclofenac and what kind of toxicity can it form?
It’s an NSAID and it can be oxidized into a quinone imine which can cause GI and liver toxicity.
Where is Eugenol present and what can it form to cause toxicity?
It’s present in cigarrette, food, cloves, and it can form quinone methide and o-quinone (if you demthylate first).
