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PHAR 202 > UDP-glucuronosyltransferases > Flashcards

UDP-glucuronosyltransferases Flashcards

1
Q

What is glucuronidation?

A

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

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2
Q

What reaction does glucuronidation facilitate?

A

A detoxification reaction that facilitates elimination from the body

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3
Q

What catalyzes glucuronidation?

A

Members of the UDP-glucuronosyltransferase (UGT) family

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4
Q

What co-substrate does glucuronidation use?

A

UDP-glucuronic acid (nucleotide sugar)

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5
Q

The three main functional groups that are glucuronidated are ________

A

Hydroxyl, carboxyl, and amine

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6
Q

Where is the main site of glucuronidation?

A

The liver

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7
Q

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

A

Tissues including kidney, lung, intestines, and skin

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8
Q

How does the xenobiotic metabolism of Phenytoin facilitate excretion?

A

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

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9
Q

Why does the UGT family have many different UGTs?

A

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

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10
Q

UGT1A proteins are all encoded by _________

A

a single gene

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11
Q

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

A

True

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12
Q

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

A

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

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13
Q

What is a drug-drug interaction?

A

When one drug interferes with the metabolism of another drug

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14
Q

What are probe substrates?

A

The identification of compounds that are glucuronidated specifically by each UGT

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15
Q

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

A

False

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16
Q

What is Bilirubin?

A

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

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17
Q

True or False: Bilirubin has potent anti-oxidant activity

A

True

18
Q

Why are anti-oxidants important?

A

Because oxidative stress can cause damage to cells

19
Q

True or False: Bilirubin is neurotoxic

A

True

20
Q

What do high blood levels in liver damage indicate?

A

Blood markers (associated with Bilirubin)

21
Q

Explain what jaundice is

A

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

22
Q

What is neonatal jaundice?

A

High levels of Bilirubin in newborn babies

23
Q

Why is exposure to light a treatment for neonatal jaundice?

A

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

24
Q

What is the major route for Bilirubin metabolism?

A

Glucuronidation

25
Q

What is Crigler-Najjar Syndrome Type I?

A

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

26
Q

What is the importance of the UGT enzyme protein?

A

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

27
Q

What is Crigler-Najjar Syndrome Type II

A

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.

28
Q

What do phototherapy and phenobarbital do?

A

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

29
Q

What is Gilbert’s Syndrome?

A

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.

30
Q

What is Irinotecan?

A

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)

31
Q

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

A

Means that the active agent SN38 is not metabolized as effectively

32
Q

What does the buildup of SN38 associated with?

A

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

33
Q

In what case can the buildup of SN38 worsen?

A

Patients who are taking other drugs that inhibit UGT1A1

34
Q

How can genetic tests help in treatment?

A

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

35
Q

What is Atazanavir?

A

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

36
Q

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

A

Higher

37
Q

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

A

Because it is a potent inhibitor of UGT1A1

38
Q

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

A

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

39
Q

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

A

Darunavir

40
Q

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

A

Darunavir

41
Q

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

A

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

PHAR 202 (8 decks)

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