From the Guidelines
Cytochrome P450 (CYP450) enzymes are a family of proteins found primarily in the liver that play a crucial role in drug metabolism, breaking down medications, toxins, and other foreign substances in the body, converting them into forms that can be more easily eliminated, with the main CYP enzyme, CYP3A4, being responsible for the metabolism of more than 50% of all drugs in the market 1.
Overview of CYP450 Enzymes
The P450 system includes multiple enzyme subtypes (such as CYP3A4, CYP2D6, and CYP2C9) that each metabolize different drugs. This is clinically important because some medications can inhibit or induce these enzymes, leading to drug interactions. For example, if one medication inhibits a P450 enzyme that metabolizes another drug, the second drug may accumulate to potentially toxic levels in the body. Conversely, if a medication induces (increases) enzyme activity, other drugs might be metabolized too quickly, reducing their effectiveness.
Clinical Importance of CYP450 Enzymes
Genetic variations in P450 enzymes also explain why people respond differently to the same medication, as some individuals naturally have higher or lower enzyme activity levels, affecting how quickly they process certain drugs. Cancer patients are particularly susceptible to drug interactions due to the high number of medications they receive, either for supportive care or for treatment of therapy-induced toxicity, with studies showing that co-prescription of drugs that induce or inhibit metabolic pathways used by tyrosine kinase inhibitors (TKIs) is high, ranging from 23-57% for drugs that may decrease TKI effectiveness and 24-74% for drugs that may increase TKI toxicity 1.
Key Points to Consider
- The main CYP enzyme, CYP3A4, is responsible for the metabolism of more than 50% of all drugs in the market 1.
- Cancer patients are susceptible to drug interactions due to the high number of medications they receive 1.
- Genetic variations in P450 enzymes can affect how individuals respond to medications 1.
- Drug interactions can lead to serious clinical consequences, such as increased toxicity or therapeutic failure, particularly in cancer patients receiving TKIs 1.
From the Research
Definition and Function of Cytochrome P450 (CYP450) Enzyme
- The Cytochrome P450 (CYP450) enzyme is a family of related enzymes involved in the metabolism of various substances, including vitamins, steroids, fatty acids, and other chemicals 2.
- These enzymes play a crucial role in the detoxification of xenobiotics, cellular metabolism, and homeostasis 3.
- CYP450 enzymes are membrane-bound hemoproteins that can be transcriptionally activated by various xenobiotics and endogenous substrates through receptor-dependent mechanisms 3.
Role in Drug Metabolism and Interactions
- CYP450 enzymes are involved in the metabolism of drugs, and their induction or inhibition can lead to drug-drug interactions 3.
- Many chemotherapeutic drugs can cause drug interactions due to their ability to either inhibit or induce the CYP450 enzyme system 3.
- Knowledge of the substrates, inducers, and inhibitors of CYP450 isoforms, as well as polymorphisms of CYP450 enzymes, can aid clinicians in determining therapeutic strategies and treatment doses for drugs metabolized by CYP450 gene products 3.
Structure and Mechanism
- Recent structural insights into CYP450 function have been obtained through studies on microbial and mammalian PYP450s 4.
- CYP450 enzymes can catalyze regio- and stereoselective oxidations of nonactivated C-H bonds in complex organic molecules under mild conditions, making them useful biocatalysts in various applications 5.
Applications and Engineering
- CYP450 enzymes have been engineered for biomedical and biotechnological applications, including the production of pharmaceuticals, fine or bulk chemicals, bioremediation agents, flavors, and fragrances 5.
- Various strategies, such as protein engineering, redox-partner engineering, substrate engineering, electron source engineering, and P450-mediated metabolic engineering, have been used to improve CYP450 systems 5.