CYPs

Cytochrome P450 enzymes (CYPs) are a large and diverse superfamily of heme-containing monooxygenases that catalyze the oxidation of a wide range of substrates. They introduce one atom of oxygen into organic substrates while reducing the other oxygen atom to water, using NADPH as an electron donor. They participate in the metabolism of endogenous compounds such as steroids, fatty acids, and bile acids, as well as xenobiotics including drugs and environmental chemicals.

In humans, most CYPs are membrane-bound proteins of the endoplasmic reticulum in hepatocytes and other tissues; a subset are located in mitochondria. They require cytochrome P450 reductase and sometimes cytochrome b5 to supply electrons for the catalytic cycle, which begins with substrate binding to the ferric heme and proceeds through a series of reductions and oxygen activation.

Nomenclature follows the CYP family and subfamily system (e.g., CYP3A4). Family members share at least 40% sequence identity; subfamilies share at least 55%. The human genome encodes many CYPs, but a small number are responsible for most drug metabolism. Major drug-metabolizing enzymes include CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2; these are highly expressed in liver and intestine and exhibit broad substrate specificities.

Genetic variation in CYP genes leads to interindividual differences in metabolic capacity. Polymorphisms can produce poor, intermediate, extensive, or ultrarapid metabolizer phenotypes, influencing drug efficacy and toxicity. For example, CYP2D6 is highly polymorphic, and genotype can guide antidepressant or opioid dosing.

CYP activity is modulated by inducers and inhibitors, producing clinically important drug interactions. Inducers such as rifampin or phenobarbital increase enzyme expression, accelerating metabolism, while inhibitors such as ketoconazole or ritonavir decrease metabolism. Grapefruit juice inhibits intestinal CYP3A4, altering oral drug bioavailability. In addition to drug metabolism, CYPs metabolize environmental chemicals and activate or detoxify procarcinogens.