Key words cytochrome p450 isoenzymes drug interactions summary introduction the cytochrome p450cyp enzyme system con. Human polymorphic enzymes and the global distribution of major variant alleles allele frequency % consequence no. The cytochrome p450 is the major enzyme involved in drug metabolism. The genetic polymorphism of cyp isoenzymes participating in drug biotransformation is presented in table 1. The aim of this study was to assess the catalytic activities of 38 human cyp2c9 alleles. Cytochrome p450 enzymes are essential for the metabolism of many medications. In the case of some cyp isoenzymes involved in drug biotransformation, e. Cytochrome p450 enzymes in drug metabolism and chemical. It is also highly expressed in areas of the central nervous system, including the substantia nigra cyp2d6, a member of the cytochrome p450 mixedfunction oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. The gene, cyp2d6, is located on chromosome 22 and mutation of this gene can result in reduced or low affinity forms of the enzyme. Cytochromes p450 cyp are a major source of variability in drug pharmacokinetics and response. Genetic polymorphism and toxicologywith emphasis on.
The polymorphic cytochrome p450 isoenzymes cyp2c9 and cyp2c19 are involved in the biotransformation of a wide variety of clinical drugs. Genetic polymorphism of drugmetabolizing enzymes cyp2c9. P450 drug metabolism i 20 university of washington. We report a patient with psychosis and hypertension related to amitriptyline, tramadol. Thus, it has been hypothesized that variants in the cyp network may influence antidepressant efficacy and safety. Cytochrome p450 polymorphism molecular, metabolic, and pharmacogenetic aspects. Sitedirected mutation studies of human liver cytochrome p450 isoenzymes in the cyp2c subfamily. Variability between individuals in the pharmacokinetics of cancer chemotherapy has important consequences in terms of therapeutic. Genetic polymorphisms of drug metabolizing enzymes give rise to distinct. Watercress is also a known inhibitor of the cytochrome p450 cyp2e1, which may result in altered drug metabolism for individuals on certain medications e. Cyp450 isoforms involved in drug metabolism are also present in kidney, lung, brain, breast, prostate and in the small intestine 17.
Genetic polymorphism of drug metabolism 325 table 1. A total of 248 drug metabolism pathways with known cyp involvement. Genetic polymorphisms of cytochrome p450 enzymes and antidepressant metabolism. A drug that is quickly metabolized is broken down sooner and a higher dose might be needed to be effective. Genetic polymorphisms of cyp2c9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. Genetic polymorphisms of cyp2c9significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure.
The complement of the various cytochrome p450 enzymes in a given individual varies markedly, and dramatic differences may be seen in drug metabolism, pharmacological response, and susceptibility to. The most intensively studied route of drug metabolism is the p450 catalysed mixedfunction. The cytochrome p450 p450 or cyp isoenzymes are a group of hemecontaining 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. Genetic polymorphism of drug metabolizing enzymes, particularly cytochrome p450 cyp, is an important cause of adverse drug reactions. Cytochrome p450, drug metabolism, genetic polymorphism, type 2 diabetes mellitus introduction type 2 diabetes mellitus t2dm, also known as adultonset or noninsulindependent diabetes, is emerging as a topic of major global concern related to the bodys ability to metabolize glucose. Warfarin, the more potent isomer, is metabolized primarily by cyp2c9. Several polymorphic cytochrome p450 isoenzymes, notably cyp2d6 and cyp2c19, are involved in metabolism and elimination of tricyclic antidepressants tcas and the selective serotonin reuptake inhibitors ssris table 7. The occurrence of genetic polymorphism has been seen in genes for cyp1a1, cyp2a6, cyp2c9, cyp2c19, cyp2d6, cyp2e1 and cyp3a5. Multiple gene mutations in cyp have been shown to be phenotype. This will enhance the use of rational drug therapy and better drug combinations. Genetic polymorphisms in the cytochrome p450 system and. Their major alleles occur with varying frequencies among different populations worldwide and have been associated with a varied capacity to degrade important therapeutic agents. A genetic defect of enzymes involved in drug metabolism, particularly cytochrome p450 cyp, has been believed to be one of the important causal factors of adverse drug reactions.
Multiple adverse drug reactions and genetic polymorphism. Genetic polymorphisms create subpopulations of patients that may require individual therapy strategies. The distribution of variant cyp2c9 alleles was therefore investigated in an italian and an ethiopian population methods allele. The effect of cytochrome p450 metabolism on drug response.
It is now clear that a significant proportion of these adverse drug reactions, as well as therapeutic failures, are caused by genetic polymorphism, genetically based interindividual differences in drug absorption, disposition. Cytochrome p450 cyp nomenclature system after the letter. Genetically determined rates of drug metabolism and thus elimination can, for many drugs, lead to variable and unpredictable responses, presenting clinically as. The cytochrome p450 cyp enzymes are the major enzymes responsible for phase i reactions in the metabolism of several substances, including antidepressant medications. P450 enzymes in drug metabolism the polymorphic p450 cyp. Cytochrome p450 p450 enzymes include a family of related enzymes that are involved in metabolism of vitamins, steroids, fatty acids, and other chemicals. Nonetheless, for some isoenzymes, such as cyp1a2 and. Participation of cyp isoenzymes in endogenous substance metabolism cyp isoenzymes participate in metabolic pathways important for proper physiological functioning of the human organism.
Genotyping for cyp polymorphisms provides important genetic information that. Implications of cytochrome p450 2c9 polymorphism on warfarin. Cyp2c8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the. Effects of cytochrome p450 2c9 polymorphism on bosentan. Selected genetic polymorphisms of human cytochromes p450 and por. During the last 1015 years, cytochrome p450 cyp 2c8 has emerged as an important drugmetabolizing enzyme. Nonetheless, data on this field are still contradictory.
A pharmacogenetic test was performed to assess the causative role of the cyp2d6 enzyme, but did not demonstrate a metabolic deficiency. For most drugmetabolizing enzymes dmes, the functional consequences of genetic polymorphisms have been examined. Defects in drug metabolic pathways could explain why some patients have a history of multiple adverse drug reactions adr. Genetic polymorphism of cyp2d6 and cyp2c19 metabolism. Among the factors, the rate of drug metabolism has been regarded as the most important one. Cytochrome p450 enzymes hemoproteins play an important role in the intracellular metabolism. Cyp enzymes are responsible for the metabolism of most clinically used drugs. Aims cyp2c9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect the therapeutic outcome during treatment with several drugs.
Genetic polymorphism of drugmetabolizing enzymes cyp2c9 and. It is now clear that a significant proportion of these adverse drug reactions, as well as therapeutic failures, are caused by genetic polymorphism, genetically based interindividual differences in drug absorption, disposition, metabolism. Extensive interindividual variation in human drug metabolism leads to a number of different outcomes in patients treated with the same drug. Increased knowledge of the mechanisms behind adrs because of allelic cytochrome p450 p450 or cyp variants is essential for efficient and safe drug treatment and for successful drug development. The cyp2d6 phenotype was determined from the ratio of dextromethorphan conversion to dextrorphan and the cyp2c19 phenotype from the ratio of smephenytoin and r. Rifampicin is a well established potent enzyme inducer and is known to induce a number of cytochrome p450 isoenzymes, including cyp3a4, and other phase ii metabolic processes, such as glucuronidation, resulting in reduced exposure to a wide variety of. For most drug metabolizing enzymes dmes, the functional consequences of genetic polymorphisms have been examined.
Role of cytochrome p450 in drug interactions nutrition. Genetic polymorphisms in cyps are a major cause of the inter individuals variation in drug metabolism. The distribution of variant cyp2c9 alleles was therefore investigated in an italian and an ethiopian population. A patient taking atorvastatin is prescribed treatment for tuberculosis including rifampicin. Influence of cyp genetic polymorphism on population differentiation of drug metabolism phenotype. Cytochrome p450 isoenzyme an overview sciencedirect topics. Of 57 putatively functional human cyps only about a dozen enzymes, belonging to the cyp1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 7080% of all drugs in clinical use. Cytochrome p450 enzymes account for 70 percent to 80 percent of enzymes involved in drug metabolism. Genetic polymorphisms in the cytochrome p450 system and efficacy of 5hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting m. The lack of therapeutic response even with standarddosage regimens of the tca nortriptyline provided one of the earliest clinical examples of how altered expression. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most. Role of cytochrome p450 2c8 in drug metabolism and. Of particular interest is genetic polymorphism in drug oxidation.
Distribution of genetic polymorphisms in drug metabolizing. Cytochrome p450 isoenzymes are regulated by both genetic and environmental factors. Pdf cytochrome p450 polymorphism molecular, metabolic. Based on knowledge of cyp isoenzymes involved in the metabolism of drugs, physicians may better anticipate drug interactions. Genetic polymorphism of cyp2d6 and cyp2c19 metabolism determ. In the current overview, we emphasize some recent findings in this area and summarize our view of the future challenges in this field. Pdf genetic polymorphisms of cytochrome p450 enzymes and. Genetic polymorphism of cytochrome p450 2c9 in a caucasian. Although metabolism mediated by cytochrome p450 isoenzymes is known to play a major part in the biotransformation of anticancer agents in vivo, few clinical studies have investigated activity of cytochrome p450s and therapeutic outcome in people with cancer. There are multiple gene mutations for cyp causing the poor metabolizer phenotype. Multiple adverse drug reactions and genetic polymorphism tes. Cytochrome p450 2d6 cyp2d6 is an enzyme that in humans is encoded by the cyp2d6 gene. Cytochrome p450, taqmanpcr, dried saliva, japanese population, genetic analysis.
Variants leading to reduced or increased enzymatic activity as compared to the. Combination analysis in genetic polymorphisms of drug. Dextromethorphan was used as the probe for cyp2d6 activity and mephenytoin was used for cyp2c19 activity. The cytochrome p450 enzymes cyps are a diverse super family of enzymes which taken together,are capable of metabolising wide variety of endogenous and xenobiotic substances including drug molecules. Genetic polymorphism of cytochrome p450 and methods for its. Implications of cytochrome p450 2c9 polymorphism on. Research paper combination analysis in genetic polymorphisms. Cytochrome p450 cyp enzymes constitute the major metabolizing enzyme system in humans, and are responsible for the metabolism of exogenous compounds, including many drugs, carcinogens, mutagens and alcohols 1,2. The 5ht 3 receptor antagonists are metabolized by cytochrome p450 cyp enzymes which constitute a family of more than 30 isoenzymes. Warfarin is an anticoagulant available as a racemic mixture. Interestingly, lossoffunction polymorphisms in cyp genes surprisingly often affect splicing and expression. Cyp3a3, cyp2c18, no cases of genetic polymorphism have been observed so far.
Cyp2c8 is highly expressed in human liver and is known to metabolize more than 100 drugs. Heritable genetic variation in drug metabolizing enzyme genes has been studied for over 60 years and many intriguing examples of the genetic influence on drug biotransformation have been investigated at great detail and for some of them clinical relevance has been studied meyer, 2004. Key words cytochrome p450 isoenzymes drug interactions summary introduction the cytochrome p450 cyp enzyme system con. The aim of this study was to assess the catalytic activities of 38 human cyp2c9 alleles, including 24 novel. Individual variability in cyp activity is one important factor that contributes to drug therapy failure. Genetic polymorphisms of cytochrome p450 2d6 cyp2d6. Several cytochrome p450 isoenzymes are associated with genetic polymorphism. The physiological and pharmacological roles of cytochrome.
Each cytochrome p450 gene is named with cyp, indicating that it is part of the cytochrome p450 gene group. Aug 01, 2007 this page will be removed from your favorites links. Most p450 genetic polymorphisms can be categorized as follows. We report a patient with psychosis and hypertension related to amitriptyline, tramadol, and duloxetine within a 2year period. The best known polymorphic isoenzyme is the cyp2d6 or debrisoquine hydroxylase enzyme 3, 12, 17. The two drugs were administered simultaneously and urine samples were collected over a period of 8 hours. Jan 17, 2012 warfarin is an anticoagulant available as a racemic mixture. Two genetic polymorphisms in drug oxidation are well known, the sparteinedebrisoquine cyp2d6 polymorphism and the mephenytoin oxidation cyp2c19 polymorphism. They lead to the occurrence of variation in response to the drugs ranging from adverse effects to lack of efficacy ingelmansundberg et al.
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