From the Guidelines
The main variations of Cytochrome P450 (CYP450) enzymes include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5, which are the most clinically significant isoenzymes involved in drug metabolism. These enzymes are primarily found in the liver and play crucial roles in metabolizing approximately 75% of all prescribed medications 1. CYP3A4 is the most abundant, metabolizing about 50% of all drugs, while CYP2D6 processes many antidepressants and antipsychotics despite comprising only 2-4% of hepatic CYP content. Genetic polymorphisms in these enzymes can create significant variations in drug metabolism between individuals, leading to classifications such as:
- Poor metabolizers
- Intermediate metabolizers
- Extensive (normal) metabolizers
- Ultrarapid metabolizers These variations explain why some patients experience toxicity at standard doses while others show inadequate therapeutic response, as seen in the context of drugs like fluoxetine and paroxetine, which are affected by CYP2D6 polymorphisms 1. Understanding a patient's CYP450 enzyme profile can help clinicians personalize medication regimens, particularly for drugs with narrow therapeutic indices like warfarin (affected by CYP2C9) or clopidogrel (requiring CYP2C19 activation) 1. The identification of these variations is crucial for minimizing adverse reactions and maximizing therapeutic efficacy, highlighting the importance of considering CYP450 enzyme profiles in clinical practice 1.
From the FDA Drug Label
The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C92 and CYP2C93 result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9 and *11 alleles in Caucasians
The main variations of Cytochrome P450 (CYP450) enzymes involved in the metabolism of warfarin are:
- CYP2C9: a polymorphic enzyme that metabolizes the S-enantiomer of warfarin to 7-hydroxywarfarin
- CYP2C19
- CYP2C8
- CYP2C18
- CYP1A2
- CYP3A4 The CYP2C9 enzyme has variant alleles, including:
- CYP2C9*2
- CYP2C9*3
- CYP2C9*5
- CYP2C9*6
- CYP2C9*9
- CYP2C9*11 2
From the Research
Main Variations of CYP450 Enzymes
The main variations of Cytochrome P450 (CYP450) enzymes include:
- CYP2C19: This enzyme has several allelic variants, including *1, *2, and *17, which can affect drug metabolism 3.
- CYP2D6: This enzyme also has several allelic variants, including *1, *2, *3, *4, *5, and *10, which can impact drug metabolism 3, 4.
- CYP2C9: This enzyme has allelic variants, including *1, *2, and *3, which can influence drug metabolism 3, 5.
- CYP1A2: This enzyme is involved in the metabolism of certain drugs, including caffeine and clozapine, and can be inhibited by fluvoxamine 4.
- CYP3A4: This enzyme is the most abundant human cytochrome P450 and is involved in the metabolism of many drugs, but is not significantly inhibited by most SSRIs 4, 6.
Classification of Metabolizers
Based on the genotype-metabolic phenotypes of CYP2C19, CYP2D6, and CYP2C9 enzymes, patients can be classified as:
- Normal metabolizers (NMs)
- Intermediate metabolizers (IMs)
- Rapid metabolizers (RMs)
- Ultrarapid metabolizers (UMs)
- Poor metabolizers (PMs) 3
Impact of Genetic Variations
Genetic variations in CYP450 enzymes can affect drug metabolism and lead to alterations in phenotypes, including toxicity, adverse drug reactions, and inefficient treatment 5, 6, 7.
- Multiallelic genetic polymorphisms can lead to distinct pharmacogenetic phenotypes, including poor, intermediate, extensive, and ultrarapid metabolizers 6.
- Genetic polymorphisms and epigenetic changes in CYP genes, as well as environmental factors, can contribute to interethnic and interindividual variations in drug response 7.