UDP-Glucuronosyl Transferases and Glucuronidation

Question 1

Define phase 2 metabolism

Answer 1

should detoxify the drug or drug metabolite and/or allow excretion through bile or through the kidneys by adding a water solubilising group

Question 2

Name the type of reactions in phase 2 metabolism

Answer 2

Glucuronidation
Glutathione conjugation (electrophiles)
Amino-acid conjugation
Sulfation
Acetylation
Methylation (rare)

Question 3

Define glucurondiation

Answer 3

Addition of glucuronic acid (an electrophile) to nucleophiles
common nucleophiles include OH groups, phenols, SH groups and carboxylate groups, amines (when basic form)

Question 4

What is the most common reaction in phase 2 metabolism?

Answer 4

the glucuronidation reaction
inversion of configuration (alpha and beta) at anomeric
variable amounts of drug can be glucuronidated

Question 5

Describe the structure of UDP-Glucuronosyl Transferase (UDPGT)

Answer 5

Found in membrane of ER as well as many tissues, especially the liver, skin, intestine, kidney, lung and adrenals and spleen

Question 6

Do drugs with a MW <200Da excreted in the urine or in the bile?

Answer 6

Urine

Question 7

Do drugs with a MW > 200 Da get excreted in the urine or in the bile?

Answer 7

Bile

Question 8

Describe how drugs are recycled in the enterohepatic circulation

Answer 8

recycled due to the presence of gut beta-D-glucuronidase
used to salvage important biochemical such as the steroid hormones
it increases the apparent half-life of the drug due to the removal of glucuronic acid and reabsorption of the drug
can get increased toxicity

Question 9

Name some common UDPGT enzymes in drug metabolism

Answer 9

• 1A1, 1A3, 1A4, 1A6, 2B4, 2B7, 2B10, 2B11, 2B15 (liver)
  
  • 1A10 (other tissues, including GI tract) – broad substrate selectivity

Question 10

How is UDPGT produced?

Answer 10

From several coding regions (exons) within the gene
UDPGTs share exons 2-5 but have a variable exon 1
polymorphisms affect drug metabolism and rate of transcription and translation or enzyme stability

Question 11

Define Gilberts Syndrome

Answer 11

UDPGT deficiency
extremely common recessive condition
defect in the elimination of the breakdown products haem so haem is oxidised and the rings are broken in order to form bilirubin
reduced activity or expressional level of UDPGT1A1

Question 12

Name the most common mutation in Caucasians who have Gilberts syndrome

Answer 12

UDPGT1A1*28 occurs in the promoter region of the gene = affects enzyme expression

Question 13

Name the most common mutation of Asians with Gilberts syndrome

Answer 13

missence - replaces an amino acid - reduces enzyme activity - substituted one amino acid for another one

Question 14

What are the consequences of Gilberts syndrome?

Answer 14

Bilirubin levels rise in the blood
can be promoted by stress and exercise, dehydration
can have periodic jaundice

affects some metabolism of drugs:
Atazanavir and indinavir
Irinotecan (anti-cancer)
Paracetamol metabolism can be reduced

Question 15

Define the drug interactions with UDPGTs

Answer 15

can occur due to 2 drugs being metabolised by the same enzyme
reduced metabolism can also result from depletion of UDP-` acid - e.g. paracetamol causes toxicity in neonates - resulting in babies experiencing yellow jaundice
can get increased metabolism due to enzyme induction from drugs such as cigarette smoke and pollutants
can get complex behaviour with chiral drugs - more than one glucuronidation site

Question 16

Describe chiral selectivity of UDPGTs

Answer 16

Different enantiomers can react with different UDPGTs - when the substrate which is being metabolised binds to the enzyme active site - diastereoisomers are formed