Phase II Lecture

Question 1

Important things that happen in phase II?

Answer 1

Covalent conjugation reactions mediated by enzymes located predominantly in the cytosol

• Attach a larger size, hydrophilic endogenous substrate to functional groups placed there by phase I
• Uses glucuronic acid, glutathione, aminoacids, acetic acid
• • Forms highly polar, water soluble products that are typically inactive as drugs and readily eliminated

Question 2

What is glucuronidation?

Answer 2

Reaction of UDP-glucornic acid with ROH to form o-glucuronides or with RNH2 to form N-clucuronides

Question 3

What is UDP-glucuronosyltransferase?

Answer 3

Microsomal enzyme found in the liver and other places
Mainly UGT1 and UGT2
Inducible by a number of compounds

Question 4

What is Gilbert’s Syndrome?

Answer 4

Defective UGT1A1
Decreased ability to conjugate bilirubin
- Usually isn’t a problem unless there is a challenge or stress added to the body (transfusion of blood or broken down RBC)

Question 5

What is enterohepatic recycling?

Answer 5

Drug-glucuronide complexes excreted into gut can be broken down by gut beta-glucuronidase within the normal flora
- Released drug can be reabsorbed into the body causing a cycle to form and prolonging the half life of drug in the body

Question 6

What is acyl glucuronide migration?

Answer 6

Migrates to a new position and during migration the pharmacologic actions can change and be toxic

Question 7

What is sulfation by sulfotransferases?

Answer 7

Critical route of metabolism for catecholamine nerotrasnmitters, steriod hormones, thyroxine, and phenolic drugs

• Utilize energy rich sulfate donor: PAPS
• High affinity, low capacity

Question 8

What is methyltransferases do?

Answer 8

Addition of a methyl via SAM

Example: COMT in metabolism of catetholamines

Question 9

So you give a cancer patient azathoprine or 6-mercaptopurine, what do you expect to happen?

Answer 9

Some of it to be broken down by XO (xanthine oxidase) and some to be broken down by TPMT (methyl transferase) and finally some to go through HPRT and other enzymes to treat the cancer by forming false nucleotides that will terminate cancer cells

Question 10

But what if the patient doesn’t have XO or TPMT capabilities?

Answer 10

You have an abnormal amount of false nucleotide groups leading to toxicitiy
– Important to test for both XO and TPMT having the right amount of capabilities

Question 11

What is acetylations?

Answer 11

Uses acetyl-CoA to transfer acetyl groups leading to the incorporation of adenosines, phosphates and Vitamin D5

Question 12

Where are acetylations most often found?

Answer 12

Kupffer cells
- part of the immune system in the liver
- Sense what is coming through the blood stream
- Very phagocytic
Full of acetyltransferase

Question 13

What is amino acid conjugations?

Answer 13

Addition of an amino acid to a group

Question 14

What is glutathione conjugation?

Answer 14

Bonds through a nucleophilic cysteine thiol group

- Very reactive with electrophilic substances

Question 15

What happens in glutathione-S-transferase?

Answer 15

Phase 1: mixed function oxidase –> forms an epoxide
Phase 2: Connects epoxide to the sulfur (connecting the glutathione)
- Glutamate is removed
- Peptisdase removes glycine
- Then the molecule can be excreted to the urine and forms a muracapturic acid

Question 16

Active ingredient of marijuana?

Answer 16

Body tries to keep the active ingredient and it prolongs the half life by making it less water soluble through the connection of a fatty acid chain

• • gets held in the fat cells and it slowly comes out in the urine
• -Body doesn’t recognize this as a drug