Cytochrome P450 Mediated Reactions Flashcards
What do drug-drug interactions often result in?
Often results in drug metabolism which can lead to;
Toxicity
Altered pharmacological effect
Why’re drugs metabolised to be more polar?
Must be made more polar for easier excretion - urine/faeces
Where is the main site of drug metabolism in the body?
The liver
What are Phase 1 metabolism reactions?
Small changes to chemical structure
Molecule is functionalised for Phase 2
What’re Phase 2 metabolic reactions?
Conjugation reactions
Large increase in water solubility & excretion
What reactions does Phase 1 metabolism involve?
Oxidation by Cytochrome P450
Non-P450 Oxidation
Reduction
Hydrolysis
What does functionalisation of drugs mean? What’re the consequences?
Addition or unmasking of a reactive group
Small reduction in lipophilicity
Slight increase in excretion
Can increase or decrease pharmacological activity
What reactions does Phase 2 metabolism involve?
Glucuronidation
Sulphation
Acetylation
Amino acid conjugation
Glutathione conjugation
What does conjugation mean in drug metabolism? What does this mean?
Addition of a large, often charged, group
Large decrease in lipophilicity
Increase in excretion
Usually decrease in pharmacological effect
What is Cytochrome P450?
CP450 is the terminal oxidase component of an electron transfer system, in the smooth endoplasmic recticulum
What does CP450 require?
Molecular oxygen
Co-factor NADPH
Cytochrome P450 reductase
What’re Cytochrome P450 enzymes also involved in?
Steroid biosynthesis and vitamin A&D metabolism
What is characteristic of CYP450 enzymes?
Have a characteristic absorption maximum at 450nm in the presence of CO
All P450s contain the prosthetic group ferriprotoporphyrin IX
What is a prosthetic group?
A non-protein structure that is bound tightly to a protein and is essential to the activity of the protein
What’re the steps of CYP450 enzyme cycle?
- Substrate binds
- Oxygen associates with Fe
- 1 x Oxygen atom forms water with 2H+
- 2nd Oxygen atom combines with substrate
- Substrate leaves active site
What type of reaction is shown?
Aliphatic hydroxylation
What type of reaction is shown?
Aromatic hydroxylation
What type of reaction is shown?
Epoxidation
What type of reaction is shown?
O-dealkylation
What type of reaction is shown?
N-dealkylation
What type of reaction is shown?
Oxidative deamination
What type of reaction is shown?
N-oxidation
What type of reaction is shown?
S-oxidation
What type of reaction is shown?
Alcohol oxidation
What type of reaction is shown?
Dehydrogenation
What type of reaction is shown?
Dehalogenation - quite rare
