UDP-glucuronosyltransferases Flashcards
What is glucuronidation?
It is an important pathway of metabolism for large numbers of small endogenous chemicals and xenobiotics
What reaction does glucuronidation facilitate?
A detoxification reaction that facilitates elimination from the body
What catalyzes glucuronidation?
Members of the UDP-glucuronosyltransferase (UGT) family
What co-substrate does glucuronidation use?
UDP-glucuronic acid (nucleotide sugar)
The three main functional groups that are glucuronidated are ________
Hydroxyl, carboxyl, and amine
Where is the main site of glucuronidation?
The liver
Besides the main site of glucuronidation, where else can UGTs be found?
Tissues including kidney, lung, intestines, and skin
How does the xenobiotic metabolism of Phenytoin facilitate excretion?
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
Why does the UGT family have many different UGTs?
Due to endobiotics: very specific enzymes are needed o perform very specific functions
UGT1A proteins are all encoded by _________
a single gene
True or False: All UGTs except the 3A and 8A families utilize UDGPA as co-substrate
True
Why is it important to know the type of UGT that specific drugs get glucuronidated by?
Because of the possibilities of having a drug-drug interaction in the system
What is a drug-drug interaction?
When one drug interferes with the metabolism of another drug
What are probe substrates?
The identification of compounds that are glucuronidated specifically by each UGT
True or False: Bilirubin is not able to cross the blood-brain barrier
False
What is Bilirubin?
End product of the breakdown of hemoglobin from aged red blood cells
True or False: Bilirubin has potent anti-oxidant activity
True
Why are anti-oxidants important?
Because oxidative stress can cause damage to cells
True or False: Bilirubin is neurotoxic
True
What do high blood levels in liver damage indicate?
Blood markers (associated with Bilirubin)
Explain what jaundice is
People with liver disease have a yellow appearance due to liver failure from the high levels of Bilirubin in their body
What is neonatal jaundice?
High levels of Bilirubin in newborn babies
Why is exposure to light a treatment for neonatal jaundice?
Because the chemical structure of bilirubin is susceptible to light, and newborn babies (neonates) have thin skin in which the light can penetrate to
What is the major route for Bilirubin metabolism?
Glucuronidation
What is Crigler-Najjar Syndrome Type I?
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
What is the importance of the UGT enzyme protein?
It metabolizes bilirubin. Too much bilirubin in the body is toxic.
What is Crigler-Najjar Syndrome Type II
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.
What do phototherapy and phenobarbital do?
Induces the expression of the UGT1A1 protein and lowers serum bilirubin levels
What is Gilbert’s Syndrome?
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.
What is Irinotecan?
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)
What does the reduced capacity for glucuronidation via UGT1A1 mean (in people with Gilbert’s syndrome)?
Means that the active agent SN38 is not metabolized as effectively
What does the buildup of SN38 associated with?
Potentially severe toxicity that can limit treatment for diarrhea and neutropenia (low neutrophil white blood cell count)
In what case can the buildup of SN38 worsen?
Patients who are taking other drugs that inhibit UGT1A1
How can genetic tests help in treatment?
Genetic tests determine patients’ UGT1A1 genotypes, which can allow tailoring of dose or the selection of alternative treatment
What is Atazanavir?
An anti-HIV drug that belongs to the class of drugs called retroviral protease inhibitors
There are ________ levels if Bilirubin in patients who are HIV positive and have Gilbert’s Syndrome
Higher
Why does Atazanavir reduce the liver’s capacity to clear bilirubin?
Because it is a potent inhibitor of UGT1A1
What possible circumstance will HIV-positive patients who are also Gilbert Syndrome patients experience?
Due to the high levels of Bilirubin in their body, they may require to discontinue their treatment
What is another protease inhibitor on the market that can be usead as a substitute for atazanavir*?
Darunavir
What is another protease inhibitor on the market that can be usead as a substitute for atazanavir*?
Darunavir
What is a positive effect of Bilirubin/Gilbert’s Syndrome?
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
