Phase II enzymes

[Ref: SH4:p15]

 

Enzymes involved in phase II reactions include:

1. Glucuronosyltransferase
2. Glutathione-S-transferase
3. N-acetyl-transferase
4. Sulfotransferase

 

Glucuronosyltransferase

Uridine diphosphate glucuronosyltransferase

• A family of hepatic microsomal enzymes
• Catalyses covalent addition of glucuronic acid to compounds
  --> More water soluble

 

Intestine contains beta-glucuronidase
--> Hydrolyse glucuronides back to parent compound
--> Reabsorbed and transport to liver for reconjugation
* Enterohepatic recirculation

 

For example,

• Propofol
  --> Glucuronidation in liver and kidney
• Opioids
  --> Undergoes glucuronidation
  * Morphine-3-glucuronide and morphine-6-glucuronide
• Midazolam
  --> Glucuronidation product 1-hydroxymidazolam (active)
  * Contribute to prolonged effect in renal insufficiency

 

Glutathione-S-transferase

Primarily a defensive system for detoxification and oxidative stress

GST-dependent activation is responsible for compound A nephrotoxicity in rats
* Absence of toxicity in human is probably a species difference

 

N-Acetyl-Transferase

• Catalyse N-acetylation
• Common phase II reaction for heterocyclic aromatic amines and arylamine hydrazine
• Responsible for inactivation of isoniazid and hydralazine
• Genetic polymorphism
  --> Fast and slow acetylators