The CYP450 enzyme system is a non-specific, mixed-function, haem-containing, oxidase enzyme system found primarily in the hepatocyte smooth endoplasmic reticulum, responsible for phase I metabolism
It makes up about 1% of total liver proteins
So-called because maximal light absorption when its reduced state is combined with carbon monoxide is 450nm
Many drugs are metabolised by more than one CYP450 enzyme
Liver
Multiple CYP isoforms, involved in drug & toxin metabolism
Some isoforms are synthetic e.g. CYP7A and CYP27A are involved in biosynthesis of bile acids from cholesterol
Kidneys
Found in the proximal convoluted tubule
Usually involved in production of arachidonic acid metabolites/prostaglandin metabolism
The CYP2C subfamily produces EET metabolites (vasodilators)
The CYP4A subfamily produces HETE metabolites (vasoconstrictors and inhibits Na+ reabsorption in the thick ascending loop of Henle)
CYP2E1 metabolises methoxyflurane, causing high local concentration of fluoride ions that have been linked with renal failure
Brain
CYP isoforms in the brain produce steroid hormones and prostaglandin metabolites
These regulate release of HPA hormones and cerebrovascular tone
Can influence mood and state of arousal via GABA receptors
Adrenal glands
CYP11, 17, 19 and 21 are involved in biosynthesis of endogenous steroids
CYP21A2 is absent in congenital adrenal hypoplasia
Other
Lung - type II pneumocytes contain CYP enzymes
GI mucosa (particularyl small bowel) - CYP3A4
Adipose tissue - CYP19 is involved in oestrogen production
CYP450 enzymes are classified and subdivided into:
Families e.g. CYP2, CYP3 [share 40% amino acid sequence]
Sub-families e.g. CYP2B, CYP2C [share 55% amino acid sequence]
Isoforms from a specific gene e.g. CYP2C9, CYP2C19
Individual alleles e.g. CYP2D6*1
CYP1 Family
The 1A sub-family is involved in metabolising polycyclic aromatic compounds such as caffeine, theophylline and propranolol
Can be induced by tobacco smoking, charbroiled meat, phenytoin and phenobarbital
CYP1A2 is strongly inhibited by ciprofloxacin and fluvoxamine and moderately so by cimetidine
CYP2 Family
CYP2 is a large family, of which 2C, 2D and 2E are most important
2C and 2D sub-families are responsible for the majority of drug metabolism
CYP2C9
Metabolises propofol, parecoxib, S-warfarin, losartan and phenytoin
Absent in 1% of Caucasians and most African-Americans
Strongly inhibited by fluconazole and moderately so by amiodarone
CYP2C19
Metabolises diazepam, omeprazole, losartan and phenytoin
Absent in 3-5% of Caucasians, 20-30% of Asians
Reduces clearance of diazepam and phenytoin
Reduced dose of omeprazole required
Strongly inhibited by PPI's, cimetidine and ketoconazole
CYP2D6
Metabolises codeine, tramadol, ondansetron, flecainide, metoprolol/atenolol, TCA and SSRI's
Absent in 7-10% of Caucasians, 1-3% of non-Caucasians
Absence may make codeine and tramadol ineffective
Genetic polymorphisms of CY2D6 may alter codeine metabolism, either increasing or decreasing its effect
Multiple copies in 30% of East Africans, who are excessive metabolisers
Non-inducible by pharmacological agents
Strongly inhibited by SSRI's, quinidine and moderately so by cimetidine and amiodarone
CYP2E1
Metabolises fluoride-containing volatile agents, ethanol and paracetamol
Not subject to pharmacogenetic variation
Induced by isoniazid and chronic alcohol use
Inhibited by disulfiram and acute alcohol use
CYP3 Family
3A is the main sub-family and accounts for 70% of GI tract CYP450
The CYP3A4 isoform metabolises fentanyl, alfentanil, lidocaine, benzodiazepines and vecuronium