Cytochrome P-450 is a "superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism."
Cytochrome P-450's role in drug metabolism is described by Wolf:
- "Nearly all lipophilic small molecules, including most drugs, which enter the body must be metabolised to more polar products before they can be excreted. This metabolic process, which is primarily catalysed by hepatic enzymes, consists of a sequence of enzymatic steps. This normally involves oxidation of the drug by the cytochrome P450-dependent monooxygenases (phase I metabolism), followed by conjugation involving sulphation, glucuronidation or acetylation (phase II metabolism)."
Common abnormal alleles
|Percentage of total human liver P450 content|
Isoforms CYP2C9, CYP2C19, and CYP2D6 account for 40% of metabolism by Cytochrome P-450.
Polymorphisms of CYP2C9 explain 10% of variation in warfarin dosing, mainly among Caucasian patients as these variants are rare in African American and most Asian populations. A meta-analysis of mainly Caucasian patients found:
- CYP2C9*2 allele:
- present in 12.2% of patients
- mean reduction was in warfarin dose was 0.85 mg (17% reduction)
- relative bleeding risk was 1.91
- CYP2C9*3 allele:
- present in 7.9% of patients
- mean reduction was in warfarin dose was 1.92 mg (37% reduction)
- relative bleeding risk was 1.77
The antilipemic agent and clofibric acid derivative gemfibrozil, may interact with warfarin due to CYP2C9. Antilipemic agents that are hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins), except for pravastatin and rosuvastatin, may also interact with warfarin, although this interaction is more likely due to CYP3A4.
Cytochrome P-450 CYP2C19 is an isoenzyme of cytochrome P-450. 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2C19 isoenzyme. More recently, a study suggests that 30% of patients may have a reduced-function allele.
CYP2C19 polymorphism affects response to clopidogrel. CYP2C19 loss-of-function alleles are associated with more cardiovascular events. Concomitant proton pump inhibitors, which are also metabolized by CYP2C19, may (especially inhibitors other than pantoprazole) or may not increase adverse cardiac events.
Poor metabolism affects many antidepressants, metoprolol and other drugs that use this isoenzyme. Some narcotics such as codeine and oxycodone are metabolized by cytochrome P-450 CYP2D6. More information is available at Entrez Gene.
CYP3A4 may metabolize over 50% of prescription drugs that are metabolized by the liver.
Antilipemic agents that are hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins), except for pravastatin and rosuvastatin, are metabolized by this isoenzyme and may:
- Increase bleeding when added to patients taking warfarin. The antilipemic agent and clofibric acid derivative gemfibrozil, may also interact with warfarin, although this interaction is more likely due to CYP2C9.
- Cause muscle injury when combined with protease inhibitors used for the treatment of human immunodeficiency virus (HIV) or hepatitis C virus (HCV). 
Antibodies to isoenzymes
|ALKM-1||CYP2D6||type 2 autoimmune hepatitis|
Various tests are available to detect abnormal metabolism.
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- Affymetrix - Drug Metabolizing Enzymes and Transporters (DMET) Plus - Campaign.
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