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Role of cytochrome P450 in drug interactions

DOI: 10.1186/1743-7075-5-27

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Abstract:

The cytochrome P450 (P450 or CYP) isoenzymes are a group of heme-containing enzymes embedded primarily in the lipid bilayer of the endoplasmic reticulum of hepatocytes, it takes part in the metabolism of many drugs, steroids and carcinogens [1]. The most intensively studied route of drug metabolism is the P450-catalysed mixed-function oxidation reaction which conforms to the following stoichiometrywhere, RH represents an oxidisable drug substrate and ROH is the hydroxylated metabolite, the overall reaction being catalysed by the enzyme P450. At the present time a number of CYP isoenzymes are expressed in each mammalian species including humans [2], many of these have specific role involving anabolic steroids and are localized in the liver. The present system of nomenclature for the various CYP isozymes employs a three-tiered classification based on the conventions of molecular biology: the family (members of the same family display > 40% homology in their amino acid sequences), subfamily (55% homology), and individual gene [3].This pedigree is indicated by, respectively, an Arabic numeral (family), a capital letter (subfamily) and another Arabic numeral (gene), e.g. CYP1A2. The enzymes transforming drugs in humans belong to the CYP families 1–4 and more than 30 human CYP isozymes have been identified to date. It has been estimated that 90% of human drug oxidation can be attributed to six main enzymes (CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4/5). The activities of the CYP2C19 [4-7] and CYP2D6 [8-14] enzymes are biomedically distributed in the population, allowing classification of individuals as either extensive (EM) or poor metabolizers (PM). The concept that most drug oxidations are catalysed primarily by a small number of P450 enzymes is important in that the approaches to identifying drug-drug interactions are feasible, both in vivo and in vitro.More side-effects of drugs and drug-drug interactions are being reported, as highly effective drugs are developed and multip

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