CytochromP450

Cytochrome P450 enzymes are a large and diverse superfamily of heme-thiolate monooxygenases that catalyze the oxidation of a wide range of endogenous and exogenous substrates. They use electrons from NADPH, transferred via NADPH-cytochrome P450 reductase (and, in mitochondria, adrenodoxin reductase), to reduce molecular oxygen and insert one oxygen atom into the substrate while the other is reduced to water.

Most human P450s are membrane-bound proteins located primarily in the endoplasmic reticulum of hepatocytes and enterocytes, with a subset found in mitochondria. They share a conserved heme cofactor with an iron center that binds oxygen during catalysis. Substrate access occurs through hydrophobic channels that vary among isoforms, enabling broad but specific substrate recognition.

Functionally, P450 enzymes metabolize endogenous compounds such as steroids, fatty acids, and bile acids, as well as numerous xenobiotics including drugs and environmental chemicals. The CYP3A, CYP2D, and CYP2C families are especially important in drug metabolism, with CYP3A4 accounting for a large proportion of hepatic and intestinal drug clearance.

Genetic variation in P450 genes contributes to interindividual differences in metabolism, leading to phenotypes such as poor, intermediate, extensive, and ultra-rapid metabolizers. Activity can be altered by induction or inhibition, producing clinically significant drug interactions; for example, rifampin induces several hepatic P450s, whereas grapefruit juice inhibits intestinal CYP3A4.

P450 enzymes also participate in the activation of certain procarcinogens and can contribute to toxicity when reactive metabolites form. The name derives from the absorbance peak of the reduced carbon monoxide-bound enzyme at about 450 nm, a property observed during early characterization in the mid-20th century.