Cytochrome P450 and Anticancer Drugs

Drug metabolism is an enzymatic biotransformation of drugs. The early stage of drug metabolism generally consists of phase I reactions such as oxidation, reduction, and hydrolysis, effected by introducing a polar group into the parent molecule. The phase I reactions are followed by conjugations with hydrophilic compounds such as glucuronic acid and glutathione, to yield a more hydrophilic metabolite (phase II reactions). Cytochrome P450 (P450 or CYP) represents the enzyme that metabolizes drugs with various manners of oxidation as the phase I reaction. P450 is comprised of a large superfamily of heme-containing membrane-binding proteins that are classified into families and subfamilies. Most of the P450 related to drug metabolisms belong to CYP1, CYP2, or CYP3 families that are known as “drug metabolizing enzymes.” Two or more P450 isoforms are frequently involved in the metabolism of the same drug, suggesting broad substrate specificity. P450 exists mainly in the liver, but may also exist in various organs such as the brain, lung, gastrointestinal tract, kidneys, and gonads. CYP3A4 is the most abundant isoform, occupying approx 30% of the total P450 amount in the human liver (1). Because many therapeutic drugs are metabolized by CYP3A4, drug interactions related to the isoform occur frequently and interindividual variation of CYP3A4 activity is sometimes clinically significant via altering pharmacokinetics and pharmacodynamic actions. Furthermore, when a drug substrate of CYP3A4 is administered orally, the CYP3A4 activity in the intestine has a clinically significant effect on the bioavailability of the drug.