CYP450s

Cytochrome P450 enzymes (CYP450s) are a large family of heme-containing enzymes that catalyze oxidation of a wide variety of substrates, including drugs, environmental chemicals, and endogenous compounds such as steroids and fatty acids. They play a central role in phase I metabolism, introducing or exposing functional groups to facilitate further processing and elimination.

Most CYP450 enzymes are located in the endoplasmic reticulum of hepatocytes and enterocytes, with a smaller mitochondrial subset. They use molecular oxygen and NADPH as electron donors, with the electrons transferred via a flavoprotein reductase system. The typical reaction is monooxygenation, inserting one oxygen atom into the substrate while reducing the other to water.

Key isoforms include CYP3A4/5, CYP2D6, CYP2C9, CYP2C19, and CYP1A2, which together account for a large portion of drug metabolism in the liver. The relative contribution of each isoform varies by substrate and individual, and activity is influenced by genetic polymorphisms, age, disease, and exposure to other chemicals.

Clinical relevance includes pharmacokinetic interactions, where induction (e.g., by rifampin or smoking) increases enzyme activity and speeds clearance of substrates, while inhibitors (e.g., ketoconazole, grapefruit juice) reduce metabolism. Genetic variants can categorize individuals as poor, intermediate, extensive, or ultra-rapid metabolizers, impacting drug dosing and response.

In addition to drug metabolism, CYP450 enzymes metabolize endogenous molecules and participate in the synthesis and breakdown of steroids and signaling lipids. Their broad substrate range and inducible nature contribute to both therapeutic efficacy and adverse reactions, making them a focal point of pharmacology and toxicology.