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Cytochrome P450 System

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The cytochrome P450 (CYP) enzymes are a superfamily of haem-containing mono-oxygenases involved in the oxidative metabolism of a wide range of xenobiotics and endogenous compounds including steroids in the body. These membrane-bound enzymes are found primarily in the liver, sited in the smooth endoplasmic reticulum (SER) of hepatocytes. CYPs are also found, to a lower extent, in extra-hepatic tissues such as the small intestine, kidney and lung where they carry out enzymatic biotransformation of foreign chemicals.

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Drug-drug interactions have become an important issue in health care. It is now realized that many drug-drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra-hepatic tissues. Many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP) enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. 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.

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Cytochrome P450 (CYP) is a hemeprotein that plays a key role in the metabolism of drugs and other xenobiotics (Estabrook, 2003). 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).

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To summarize, pharmacokinetic interactions involve the effect of one drug on the absorption, metabolism, excretion or protein binding of another drug. On the other hand, pharmacodynamic interactions are caused by several effects (additive, synergistic or antagonistic effects) of the combined treatment at the site of biological activity, changing the pharmacological action of the drugs, even at standard blood concentrations. Pharmacokinetic interactions focused on P450 are described in this paper. 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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Estabrook Ronald W. A passion for P450s (rememberances of the early history of research on cytochrome P450). Drug metabolism and disposition: the biological fate of chemicals. 2003;

Gibson G. G., Skett P. Introduction to Drug Metabolism (3rd ed.) Hampshire, UK: Nelson Thornes Ltd; 2001.

Haouala Amina, Widmer Nicolas, Duchosal Michel A, Montemurro Michael, Buclin Thierry, Decosterd Laurent A. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011

Kirchheiner J, Schmidt H, Tzvetkov M, Keulen J-T H A, Lötsch J, Roots I, Brockmöller J. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. The pharmacogenomics journal. 2007

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