L3 (UGTs)

Question 1

True or false?
UDP-glucuronosyltransferases (UGTs) is Important Enzymes that Mediate Phase II Drug Biotransformation

Answer 1

True ✅

Question 2

Complete
UDP-glucuronosyltransferases (UGTs) which has three main roles :

Answer 2

1/Drug Glucuronidation by UGT Enzymes
2/Multiplicity of the Human UGT System
3/Role of UGT1A1 in Clearance of Bilirubin and Irinotecan

Question 3

True or false?

UGT enzymes catalyze the glucuronidation of polar aglycones that contain phenolic, alcoholic, or carboxylic oxygen atoms and a limited
number of nitrogen- and sulfur-containing molecules.

Answer 3

True ✅

Question 4

UGT enzymes are active on some drugs, xenobiotics and endobiotics
such as bilirubin, steroid, and thyroid hormones.

Answer 4

True ✅

Question 5

True or false?
Multiplicity of the Human UGT System :

UGT gene subfamilies: UGT 1A,UGT 2A, and UGT 2B.

Answer 5

True ✅

Question 6

True or false?
Multiplicity of the Human UGT System :

Identified human UGTs : UGT 1A1, 1A3–1A10, 2A1, 2A2, 2B4, 2B7,
2B10, 2B11 , 2B15, 2B17, and 2B28.

Answer 6

True ✅

Question 7

True or false?
Multiplicity of the Human UGT System :
ALL UGT enzymes are expressed in liver except UGT 1A7, 1A8 and 1A10 expressed exclusively in the gastrointestinal tract . Also , UGT 2A1 is expressed in the nasal epithelium where it is involved
in the termination of signaling by odorant molecules.

Answer 7

True ✅

Question 8

Complete

Multiplicity of the Human UGT System :

UGT2B7 is functionally the most important enzyme in drug glucuronidation of

Answer 8

1/opioids
2/(NSAIDs),
3/analgesics,
4/anti-epileptic agents,
5/oncology agents,
6/anti-retrovirals,
7/hypo-lipidemic agents.

Question 9

True or false?
Multiplicity of the Human UGT System :

UGT1A1 has a major role in the glucuronidation of the heme degradation product bilirubin.so, Defects in the UGT1A1 gene impair bilirubin conjugation, leading to
hyperbilirubinemia.

Answer 9

True ✅

Question 10

Complete:
There are three levels of UGT1A1 deficiency have been identified:

Answer 10

1. Crigler–Najjar syndrome type 1
2. Crigler–Najjar syndrome type 2
3. Gilbert syndrome

Question 11

True or false?

Crigler–Najjar syndrome type 1 is characterized by :
1/most severe
2/potentially lethal hyper bilirubinemia
3/serum bilirubin >0.34 mM
4/occurs
in the absence of hemolysis or other liver disease.

Answer 11

true ✅

Question 12

True or false?
Crigler–Najjar syndrome type 2 is :
1/intermediate form of hyperbilirubinemia
2/serum bilirubin 0.12–0.34 mM
3/characterized by residual UGT1A1 activity

Answer 12

true ✅

Question 13

True or false ?

Gilbert syndrome is characterized by :
1/mildest form
2/serum bilirubin levels fluctuate up to 0.085 mM.

Answer 13

true ✅

Question 14

True or false ?

In Caucasian, African American, and South Asian populations the exon
sequences of the UGT1A1 gene are normal but the TATAA element in the 5′-
upstream region exhibits a variable number of tandem repeat polymorphism.

Answer 14

True ✅

Question 15

True or false ?

UGT1A1*28 promoter variant carries the sequence A(TA) 7TAA in place of
the wild-type A(TA) 6TAA, which decreases the transcription rate of the
UGT1A1 gene and results in defective bilirubin glucuronidation.

Answer 15

True ✅

Question 16

True or false ?

Around 10% of Caucasians are homozygous and about 40% are
heterozygous for the UGT1A1*28 variant.

Answer 16

True ✅

Question 17

True or false ?

Irinotecan is a topoisomerase II inhibitor that is the first-line treatment for
metastatic colorectal cancer. It is a prodrug that is converted by carboxylesterases to the active metabolite SN-38. SN-38 undergoes UGT1A1-mediated glucuronidation to 10-O-glucuronyl-SN-38
(SN-38G), which limits the duration of action of the drug.

Answer 17

True ✅

Question 18

True or false ?

UGT1A1 activity is a major factor that influences the extent of SN-38G formation and irinotecan toxicity. Thus, there is Close associations between the UGT1A1*28 polymorphism and predisposition to
irinotecan toxicity .

Answer 18

True ✅

Question 19

True or false ?

Plasma ratio of SN-38G: SN-38 has been related to the incidence of neutropenia
and diarrhea. Severe grade diarrhea induced by irinotecan does not respond to loperamide treatment and may necessitate hospitalization, as well as irinotecan dose
interruption.

Answer 19

True ✅

Question 20

True or false ?

Mortality from irinotecan therapy is significant in up to 5% of patients who
receive single-agent therapy.
This leads that US FDA to recommend a dose reduction for irinotecan in
individuals who are homozygous for this variant.
The association between UGT1A1 gene defects and impaired conjugation
of both bilirubin and SN-38 suggests that hyperbilirubinemia might be a
predictor of irinotecan toxicity.

Answer 20

True ✅

Question 21

True or false?

UGT Pharmacogenetics and the Incidence of Drug-Induced Hyperbilirubinemia Individuals with Gilbert syndrome who carry UGT1A1 polymorphisms may be
susceptible to drug-induced hyperbilirubinemias. Tranilast (anti-allergic drug); tranilast-mediated hyper-bilirubinemia was more prevalent in carriers of UGT1A1*28.

Answer 21

True ✅

Question 22

True or false ?

A higher incidence of jaundice in patients who received atazanavir or
indinavir and who were homozygous for UGT1A128.
This would provide insight into whether genotyping for UGT1A128 or
other UGT1A gene variants before initiation of antiretroviral therapy might assist in identifying HIV-infected individuals who are at risk from drug-
induced jaundice.

Answer 22

true ✅