Phase I enzymes

[Ref: SH4:p15]

Enzymes involved in phase I reactions include:

1. Cytochrome P-450 enzymes
2. Non-cytochrome P-450 Enzymes (Esters)
3. Flavin-containing monooxygenase enzymes

 

1. Cytochrome P-450 enzymes

aka mixed function oxidase system, or monooxygenases

• Superfamily of membrane-bound heme proteins
  * Predominantly hepatic microsomal enzymes
  * Some mitochondrial P-450 enzymes
• When combined with carbon monoxide
  --> peak absorption at 450nm
• Involved in both oxidation and reduction
• Functions as the terminal oxidase in the electron transport scheme

 

Grouping of cytochrome P-450 enzymes

• Enzymes that share more than 40% of sequence homology
  --> Grouped into a family
  * e.g. CYP2
• Enzymes that share more than 55% of sequence homology
  --> Grouped into a subfamily
  * e.g. CYP2A
• Individual enzymes are then assigned an individual number
  * e.g. CYP2A6

 

Actions of cytochrome P-450 enzymes

• 10 isoforms of cytochrome P-450 are responsible for the oxidative metabolism of most drugs
• Most CYP activities are generated by CYP2D6, CYP3A4, CYP3A5

CYP3A4

• Most abundant
• Comprising 20% to 60% of total P-450 activity

 

CYP3A4 + CYP3A5
--> Responsible for metabolism of more than half of the currently available drugs
* e.g. opoids (alfentanil, sufentanil, fentanyl)
* e.g. benzodiazepines, local anaesthetics (lidocaine, ropivacaine)
* e.g. immunosuppresants (cyclosporine), antihistamines (terfenadine)

• Gender dependent
  --> Clearance of some drugs are 20-40% higher in women
  * Due to stimulation by steroid hormone

CYP2D6

Responsible for 25% of drugs

e.g. analgesics, antidysrhythmics, amide local anesthetics, ketamine, propofol, antiemetics, and betablocker

 

For example,

• Codeine is converted to morphine and morphine-6-glucuronide
  * By CYP2D6-mediated O-demethylation
• Quinidine inhibits CYP2D6
  --> Markedly diminishes effect of codeine

 

Cytochrome P-450 and neonates

Hepatic microsomal enzyme activity is low in neonates
* especially premature infants
--> Interferes with conjugation
--> Hyperbilirubinaemia of the neonate and risk of bilirubin encephalopathy

Cytochrome P-450 and enzyme induction

• Hepatic microsomal enzyme activity can be stimulated by drugs/chemicals
• Also occurs (to limited extent) in lungs, kidney, and GIT

 

For example,

• Phenobarbital
• Polycyclic hydrocarbons (e.g. in cigarette smoke)

NB:

May increase risk of halothane hepatotoxicity

 

2. Noncytochrome P-450 enzymes (esters)

aka nonmicrosomal enzymes

• Involved in conjugation, hydrolysis
  * All conjugation reactions (except for conjugation of glucuronic acid)
• Also involved (to less extent) in oxidation and reduction
• Present mainly in liver, also plasma and GIT
• (Plasma cholinesterase and acetylating enzymes) Do NOT undergo enzyme induction
  * Activity level determined genetically

 

For example,

• Hydrolysis of drugs containing ester bonds
  * Includes succinylcholine, atracurium, mivacurium, esmolol, ester local anaesthetics

Atypical cholinesterase

• Genetic mutation
• Glycine is substituted for an aspartate in anionic binding site
  --> Loss of electrostatic interaction
  --> Less drug-substrate binding
  --> Dramatically increased duration of action for drugs such as succinylcholine and mivacurium

 

3. Falvin-containing monooxygenase enzymes

• Nicotinamide-adenine dinucleotide (NAD)-dependent microsomal enzymes
• Oxidise nitrogen, sulfur, and phosphorus-containing compounds

 

For example,

• FMO3 catalyzes oxidation of tricyclic antidepressants and H2 antagonists