BMP: Drug metabolism 2 Flashcards
What enzymes are used in phase 2 reactions?
What happens?
What type of reaction is it?
Instead of oxidases in phase 1, transferases are used in phase 2
There is transfer of a small polar molecule to the drug molecule to make it more water soluble e.g. acetate, glutathione, sulfate, glucuronate
Conjugation - product called conjugate
- Where does Aceylation mainly take place?
- What enzyme cataylases it
- Liver
- N-acteyl transferase
Give examples of acetylation in the body
What is the danger of this
- Krebs cycle - Acetyl groip from acetyl coA transferred to oxaloacteate to form citrate
- Histone acetyl transferance transferease acetyl groups to histones in DNA molecules which increase gene expression - Occurs during DNA transcription (Histone acetylation)
- acetyl- Sulphonamides are less soluble than parent compound and may cause renal toxicity due to precipitation in the kidneys
- What does phase II metabolism tend to do?
- What order does phase metabolism occur in?
- Conjugation with an endogenous substrate increases aqueous solubility
- Phase 1 then 2 normally
What is the most common phase II reaction
What happens?
•Glucuronidation
conjugation to a-d-glucuronic acid
In phase II
- Where are most producst excreted
- How many genetic family members is there
- What is metabolised?
- Bile
- 16
- exodongenous and endogenous compunds
What happens in glucuronidation?
- Enterohepatic recycling may occur due to gut glucuronidases
- Requires enzyme UDP-glucuronosyltransferase (UGT):
- The glucuronidation reaction consists of the transfer of the glucuronosyl group from uridine 5’-diphospho-glucuronic acid (UDPGA)
- process occurring with breaking down red blood cells and bilirubin.
- bilirubin is metabolised by urodine diphosphate glucuronosyltransferase and modified to a water-soluble form. This is known as ‘conjugated’ bilirubin.
- What happens in sulfation?
- What is this a major pathway for?
- What is the enzyme involved?
- Sulfate group transferred to substrate by sulfotransferases
- aryloamine, alcohol, phenol sulfotransferases fairly non-specifici
- Steriod sulfotransferases very specific
- Phenols, alcohols, thiols, amine
- PAPs (3’-Phosphoadenosine-5’-phosphosulfate)
Whats the relatioship between Glucuronidation and sulfation?
- Sulfation and glucuronidation are competing pathways:
- Sulfation predominates at low substrate concentrations
- Glucuronidation predominates at higher concentrations
- There is relatively less PAPS in cell cytosol compared to UDPGA
- What happens in glutathione conjugation and what is the enzyme involved?
- What is the purpose of this reaction?
- What futher reactions can these drugs undergo?
4.
- Tripeptide Gly-Cys-Glu; conjugated by glutathione-S-transferase (GST)
- Glutathione is a protective factor for removal of potentially toxic compounds
- Conjugated compounds can subsequently be attacked by g-glutamyltranspeptidase and a peptidase to yield the cysteine conjugate => product can be further acetylated to N-acetylcysteine conjugate
Describe Fatty acid conjugation
Steriac and palmitic acid are conjugated to drugs by esterification
Occurs in liver microsomal fraction
Describe AA conjugation
ATP-dependent acid: CoA ligase forms active CoA-amino acid conjugates which then react with drugs by N-Acetylation:
–Usual amino acids involved are:
•Glycine. Glutamine, Ornithine, Arginine
Describe methylation
- •Methylation
- •Mainly involves endogenous substrates, noradrenaline, catechols, histamine etc
- •Methyltransferases, in adrenals, liver, kidney, skin, lung e.g. N-methyltransferase
- •Require S-adenosylmethionine (SAM) as cofactor, akin to PAPS & UDPGA high energy intermediates.
- •Products are less polar than the substrate
What are the problems with phase II metabolism
•Capacity Limited Conjugations
- •Phase II conjugation reactions are frequently capacity limited by the availability of the endogenous compound required for conjugation with parent drug.
- •Sulfate, glutathione and glucuronic acid are required for the conjugation and excretion of endogenous compounds e.g. steroids & bile acids.
- •High doses of drugs coupled with low /inadequate levels of potential conjugate compounds can lead to drug accumulation and toxicity.
IMPORTANT SUMMARY
