What are Cytochrome P450 (CYP450) enzymes?

From the Guidelines

Cytochrome P450 enzymes are a large family of proteins found primarily in the liver that play a crucial role in drug metabolism and detoxification, with the most important enzymes including CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2C19, as highlighted in a study published in the British Journal of Pharmacology 1. These enzymes are responsible for breaking down approximately 75% of all medications by adding oxygen molecules to drug compounds, making them more water-soluble and easier to eliminate from the body. The main CYP enzyme, CYP3A4, is responsible for the metabolism of more than 50% of all drugs in the market, and is also implicated in the metabolism of almost all of the tyrosine kinase inhibitors (TKIs), as noted in a study published in the British Journal of Pharmacology 1. Genetic variations in these enzymes can cause individuals to metabolize drugs either too quickly or too slowly, leading to treatment failure or toxicity. Additionally, certain medications, foods (like grapefruit juice), and herbs (like St. John's Wort) can inhibit or induce these enzymes, creating drug interactions that alter medication effectiveness, as discussed in a study published in the Mayo Clinic Proceedings 1. Some key points to consider include:

• The importance of CYP3A4 in drug metabolism, with a study published in the British Journal of Pharmacology noting that it is responsible for the metabolism of more than 50% of all drugs in the market 1
• The role of genetic variations in CYP450 enzymes in affecting drug metabolism, as highlighted in a study published in the Mayo Clinic Proceedings 1
• The potential for drug interactions with CYP450 enzymes, as noted in a study published in the British Journal of Pharmacology 1 Understanding a patient's P450 enzyme activity is increasingly important in personalized medicine, allowing healthcare providers to select appropriate medications and dosages based on an individual's metabolic profile, as discussed in a study published in the Mayo Clinic Proceedings 1.

From the Research

Definition and Function of Cytochrome P450 Enzymes

• Cytochrome P450 enzymes are a superfamily of heme-thiolate proteins that play a crucial role in the metabolism of various substances, including drugs, environmental pollutants, and endogenous compounds 2.
• These enzymes are capable of catalyzing a wide range of reactions, including oxidative, peroxidative, and reductive metabolism, and are involved in the biosynthesis of various natural products 3.
• Cytochrome P450 enzymes are membrane-bound hemoproteins that are primarily expressed in the liver and intestine, where they mediate phase I metabolism and first-pass metabolism 4, 5.

Role in Drug Metabolism

• Cytochrome P450 enzymes are responsible for the metabolism of approximately 80% of oxidative metabolism and 50% of the overall elimination of commonly used drugs 4, 5.
• These enzymes can affect drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action 4.
• Genetic polymorphisms and epigenetic changes in CYP genes, as well as environmental factors, can contribute to interindividual and interethnic variations in drug metabolism and response 4, 6.

Clinical Significance

• Cytochrome P450 enzymes play a critical role in the detoxification of xenobiotics, cellular metabolism, and homeostasis, and their induction or inhibition can underlie drug-drug interactions 6.
• Knowledge of the substrates, inducers, and inhibitors of CYP isoforms, as well as polymorphisms of CYP enzymes, can aid clinicians in determining therapeutic strategy and treatment doses for drugs that are metabolized by CYP gene products 6.
• The study of cytochrome P450 enzymes is essential for understanding the mechanisms of drug metabolism and for the development of new drugs and therapies 2, 4, 5, 6.