Human cytochrome P450 (CYP)

Human cytochrome P450 (CYP) enzymes represent a massive superfamily of heme-containing proteins primarily responsible for the Phase I metabolism of approximately 70-80% of clinical drugs [1, 2]. Located predominantly in the liver and intestines, these enzymes catalyze oxidative, peroxidative, and reductive reactions to increase the water solubility of lipophilic compounds, facilitating their eventual excretion [3]. Beyond xenobiotic metabolism, CYPs play critical roles in the biosynthesis of endogenous molecules such as steroid hormones, cholesterol, and bile acids [1]. The clinical significance of CYPs is underscored by their high degree of genetic polymorphism, which leads to significant inter-individual variability in drug response, categorized into poor, intermediate, extensive, and ultrarapid metabolizer phenotypes [2, 3]. Many drugs are potent inhibitors or inducers of specific CYP isoforms, such as CYP3A4, CYP2D6, or CYP2C9, making them a primary focus for predicting and managing complex drug-drug interactions [4]. Consequently, understanding CYP activity is essential for drug development, personalized medicine, and ensuring patient safety during multi-drug regimens [2, 4]. Sources: [1] Guengerich, F. P. (2008) Chem Res Toxicol; [2] Lynch, T., & Price, A. (2007) Am Fam Physician; [3] Zanger, U. M., & Schwab, M. (2013) Pharmacol Ther; [4] FDA Drug Development and Drug Interactions (2020).

Other names

CYP450Cytochrome P450Heme-thiolate monooxygenaseMicrosomal oxidaseP450 superfamily

Drugs interact with cytochrome P450 enzymes as substrates, inhibitors, or inducers. Substrates undergo oxidative transformation (Phase I metabolism) to increase polarity for excretion [1]. Inhibitors bind to the heme iron or the active site, reducing the enzyme's ability to metabolize other drugs, which can lead to toxicity [2]. Inducers increase the expression of CYP genes via nuclear receptors like PXR or CAR, accelerating the metabolism of co-administered drugs and potentially leading to therapeutic failure [3].