Cytochrome P450 System
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However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple-drug therapies. In future, it may help to identify individuals at greatest risk of drug interactions and adverse events. 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. The most intensively studied route of drug metabolism is the P450-catalysed mixed-function oxidation reaction which conforms to the following stoichiometry where, 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, 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. More side-effects of drugs and drug-drug interactions are being reported, as highly effective drugs are developed and multiple-drug therapies are increasingly used. Drug interactions involving the P450 isoforms generally are of two types: enzyme induction or enzyme inhibition. Common substrates, inhibitors and inducers of P450 isozymes. Enzyme inhibition reduces metabolism, whereas induction can increase it. In general, high-extraction drugs are less affected by these interactions than low-extraction drugs.
Understanding the CYP system is essential for advanced practitioners (APs), as the consequences of drug-drug interactions can be profound. In this article, we will describe the CYP system, its potential for drug interactions, and the genetic polymorphisms that can exist in hematology/oncology patients. Drug metabolism occurs in many sites in the body, including the liver, intestinal wall, lungs, kidneys, and plasma. As the primary site of drug metabolism, the liver functions to detoxify and facilitate excretion of xenobiotics (foreign drugs or chemicals) by enzymatically converting lipid-soluble compounds to more water-soluble compounds. Drug metabolism is achieved through phase I reactions, phase II reactions, or both. The most common phase I reaction is oxidation, which is catalyzed by the CYP system (Gibson & Skett, 2001). Klingenberg first discovered CYP in 1954 during his research on steroid hormone metabolism, when he extracted a novel protein from hepatocytes (Klingenberg, 1958). It was almost a decade later that the function and significance of CYP were determined. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. Cooper and colleagues later confirmed CYP to be a key enzyme involved in drug and steroid hydroxylation reactions (Cooper, Levin, Narasimhulu, Rosenthal, & Estabrook, 1965). Numerous CYP proteins have since been discovered and found to be widespread throughout the body, demonstrating significant involvement in chemical activation, deactivation, and carcinogenesis (Estabrook, 2003).
The incidence of side-effects is markedly higher in the elderly and those with more severe symptoms. Thus, understanding the mechanism underlying drug interactions is useful, not only in preventing drug toxicity or adverse effects, but also in devising safer therapies for disease.
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