P450dependent

P450-dependent refers to enzymes and systems that rely on cytochrome P450 enzymes to catalyze oxidation reactions. Cytochrome P450s are heme-containing monooxygenases that insert one atom of oxygen into substrates while reducing the other oxygen atom to water, using electrons donated by NADPH through a P450 reductase and often supplemented by cytochrome b5.

Most P450-dependent reactions occur in the endoplasmic reticulum of hepatic and other cells, but these enzymes are widespread. They metabolize a broad range of substrates, including endogenous compounds such as steroids, fatty acids, and bile acids, as well as xenobiotics like drugs, environmental chemicals, and toxins. P450 enzymes exhibit broad substrate specificity and catalyze diverse reactions, including hydroxylation, epoxidation, N- and S-oxidation, desaturation, and dealkylation. Through these transformations, P450s can both detoxify and activate compounds, sometimes generating reactive intermediates.

In humans, the cytochrome P450 gene superfamily (CYP) comprises many enzymes, with CYP1, CYP2, and CYP3 families playing major roles in drug metabolism. Expression of P450 enzymes is modulated by various substances; induction can alter drug pharmacokinetics and lead to drug interactions, while inhibition can increase exposure to coadministered agents. Genetic polymorphisms contribute to interindividual variability in enzyme activity, impacting drug response and toxicity.

Mechanistically, the catalytic cycle begins with substrate binding and successive electron transfers from NADPH via P450 reductase to the heme iron, allowing oxygen binding and activation. Formation of a highly reactive iron-oxo species enables insertion of one oxygen atom into the substrate, with the second oxygen atom reduced to water and the enzyme returned to its resting state.