UDP-glucuronosyltransferases

Question 1

What is glucuronidation?

Answer 1

It is an important pathway of metabolism for large numbers of small endogenous chemicals and xenobiotics

Question 2

What reaction does glucuronidation facilitate?

Answer 2

A detoxification reaction that facilitates elimination from the body

Question 3

What catalyzes glucuronidation?

Answer 3

Members of the UDP-glucuronosyltransferase (UGT) family

Question 4

What co-substrate does glucuronidation use?

Answer 4

UDP-glucuronic acid (nucleotide sugar)

Question 5

The three main functional groups that are glucuronidated are ________

Answer 5

Hydroxyl, carboxyl, and amine

Question 6

Where is the main site of glucuronidation?

Answer 6

The liver

Question 7

Besides the main site of glucuronidation, where else can UGTs be found?

Answer 7

Tissues including kidney, lung, intestines, and skin

Question 8

How does the xenobiotic metabolism of Phenytoin facilitate excretion?

Answer 8

The xenobiotic metabolism done by the enzymes CYP450 and UDP make the drug more water-soluble, which helps the drug be excreted through urine or bile

Question 9

Why does the UGT family have many different UGTs?

Answer 9

Due to endobiotics: very specific enzymes are needed o perform very specific functions

Question 10

UGT1A proteins are all encoded by _________

Answer 10

a single gene

Question 11

True or False: All UGTs except the 3A and 8A families utilize UDGPA as co-substrate

Answer 11

True

Question 12

Why is it important to know the type of UGT that specific drugs get glucuronidated by?

Answer 12

Because of the possibilities of having a drug-drug interaction in the system

Question 13

What is a drug-drug interaction?

Answer 13

When one drug interferes with the metabolism of another drug

Question 14

What are probe substrates?

Answer 14

The identification of compounds that are glucuronidated specifically by each UGT

Question 15

True or False: Bilirubin is not able to cross the blood-brain barrier

Answer 15

False

Question 16

What is Bilirubin?

Answer 16

End product of the breakdown of hemoglobin from aged red blood cells

Question 17

True or False: Bilirubin has potent anti-oxidant activity

Answer 17

True

Question 18

Why are anti-oxidants important?

Answer 18

Because oxidative stress can cause damage to cells

Question 19

True or False: Bilirubin is neurotoxic

Answer 19

True

Question 20

What do high blood levels in liver damage indicate?

Answer 20

Blood markers (associated with Bilirubin)

Question 21

Explain what jaundice is

Answer 21

People with liver disease have a yellow appearance due to liver failure from the high levels of Bilirubin in their body

Question 22

What is neonatal jaundice?

Answer 22

High levels of Bilirubin in newborn babies

Question 23

Why is exposure to light a treatment for neonatal jaundice?

Answer 23

Because the chemical structure of bilirubin is susceptible to light, and newborn babies (neonates) have thin skin in which the light can penetrate to

Question 24

What is the major route for Bilirubin metabolism?

Answer 24

Glucuronidation

Question 25

What is Crigler-Najjar Syndrome Type I?

Answer 25

It is the most severe and most rare genetic condition that is caused by the mutations in the UGT1A1 gene, which results in the complete absence of UGT enzyme protein. The build-up of bilirubin in the body can cause kernicterus (brain damage). Type I can be treated with phototherapy/exchange transfusions/liver transplant

Question 26

What is the importance of the UGT enzyme protein?

Answer 26

It metabolizes bilirubin. Too much bilirubin in the body is toxic.

Question 27

What is Crigler-Najjar Syndrome Type II

Answer 27

It is similar to Type I wherein the case of having this genetic condition is very rare. It is caused by the mutation in the UGT1A1 gene and results in the reduced level of UGT1A1 enzyme protein (unlike in Type I where it is completely absent). Treatment includes phototherapy (for infants) and phenobarbital.

Question 28

What do phototherapy and phenobarbital do?

Answer 28

Induces the expression of the UGT1A1 protein and lowers serum bilirubin levels

Question 29

What is Gilbert's Syndrome?

Answer 29

A lot more common as compared to C-N Type I and Type II. Most people have two copies of UGT1A1*28 (which interferes with the expression and levels of UGT1A1 protein and reduces enzyme activity up to 70%). People with Gilbert's Syndrome have no symptoms and no treatment is required for this condition.

Question 30

What is Irinotecan?

Answer 30

It is an anti-cancer drug used to treat colorectal cancer. Irinotecan is an inhibitor of topoisomerase I (involved in DNA replication). It is also a prodrug that requires metabolism to the pharmacologically active agent SN38 (SN38 is metabolized by UGT1A1, as well as by UGTs 1A7 and 1A9)

Question 31

What does the reduced capacity for glucuronidation via UGT1A1 mean (in people with Gilbert's syndrome)?

Answer 31

Means that the active agent SN38 is not metabolized as effectively

Question 32

What does the buildup of SN38 associated with?

Answer 32

Potentially severe toxicity that can limit treatment for diarrhea and neutropenia (low neutrophil white blood cell count)

Question 33

In what case can the buildup of SN38 worsen?

Answer 33

Patients who are taking other drugs that inhibit UGT1A1

Question 34

How can genetic tests help in treatment?

Answer 34

Genetic tests determine patients’ UGT1A1 genotypes, which can allow tailoring of dose or the selection of alternative treatment

Question 35

What is Atazanavir?

Answer 35

An anti-HIV drug that belongs to the class of drugs called retroviral protease inhibitors

Question 36

There are ________ levels if Bilirubin in patients who are HIV positive and have Gilbert’s Syndrome

Answer 36

Higher

Question 37

Why does Atazanavir reduce the liver's capacity to clear bilirubin?

Answer 37

Because it is a potent inhibitor of UGT1A1

Question 38

What possible circumstance will HIV-positive patients who are also Gilbert Syndrome patients experience?

Answer 38

Due to the high levels of Bilirubin in their body, they may require to discontinue their treatment

Question 39

What is another protease inhibitor on the market that can be usead as a substitute for atazanavir*?

Answer 39

Darunavir

Question 40

What is another protease inhibitor on the market that can be usead as a substitute for atazanavir*?

Answer 40

Darunavir

Question 41

What is a positive effect of Bilirubin/Gilbert's Syndrome?

Answer 41

High levels/potent anti-oxidant properties, reduced risk of coronary artery disease, peripheral artery disease, and ischemic stroke, and protection against cardiovascular complications of diabetes