Cytochrom P450: CYP2C9Determination of the predisposing alleles for warfarin hypersensitivity CYP2C9*2 and kit CYP2C9*3. RDB2075 |
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| CLINICAL RELEVANCE Phase 1 and 2 enzymes of the liver Many drugs and endogenous compounds are metabolized via a small number of metabolic pathways by enzymes localized in the liver. Phase 1 reactions involve oxidation, reduction or hydrolysis. Enzymes of Phase 2 reactions conjugate by glucuronidation, sulphation, acetylation ect.. The result of all these reactions is the conversion of drugs into more polar, water-soluble compounds which can be easily excreted from the body (1). There is a extensive inter-individual variation in human drug metabolism. Individuals can sometimes be divided in low, extensive, rapid or ultrarapid metabolizer. This can lead to therapeutic difficulties or even failure (2). The main cause for the variation in drug metabolism is genetic polymorphism of the genes of phase 1 and 2 enzymes. Polymorph means, there exist different alleles of a gene in a population. Cytochrome P450 The cytochrom P450 (CYP) family of heme monooxygenases comprise the most important group of phase 1 enzymes. These enzymes oxidate a wide range of endogenous as well as exogenous compounds using atmospheric oxygen (O2) (4). The cytochrome P450 gene family contains 60 to 100 differents genes, of which only a small group is involved in drug and chemical transformations (3). The most important P450 isoenzyme is CYP3A4 (50% of the P450 metabolism) followed by CYP2D6 (20%), CYP2C9 and CYP2C19 (together 15%). The remaining is carried out by CYP2E1, CYP2A6 and CYP1A2 (3,5). The genes for CYP2D6, CYP2C9, CYP2C19 and CYP2A6 are functionally polymorphic. Therefore approximately 40% of human P450 dependent drug metabolism is carried out by polymorphic enzymes (3) (for a list of all currently known cytochrome P450 gene alleles go to http://www.imm.ki.se/ CYPalleles/). CYP2C9 Beside the wildtype allele CYP2C9*1 there are two additional alleles described, CYP2C9*2 und *3 (6, http://www.imm.ki.se/CYPalleles/). In both mutated alleles a pointmutation leads to a substitution of an aminoacid in the protein. In CYP2C9*2 an arginin at position 144 is converted to a cysteine (R144C), in CYP2C9*3 an isoleucine at position 359 is converted to a leucine (I359L) (6). The CYP2C9*3 variant is less than 5% as efficient as the wildtype enzyme, while CYP2C9*2 shows about 12% of wildtype activity (7,8). Under Caucasians about 19% are heterozygous for CYP2C9*1/*2 and 3% homozygous CYP2C9*2/*2, 15% are heterozygous CYP2C9*1/*3 and only 1% homozygous CYP2C9*3/*3 (6,9). Cytochrome P450 CYP2C9 catalysis the metabolism of important drugs such as phenytoin (antiepileptic), tolbutamide (antidiabetic), losartan (angiotensin II receptor antagonist), warfarin (antikoagulant), diazepam (anti-inflammatory) (3,6). A comprehensive list of all known substrates including references can be found on the side http://medicine.iupui.edu/flockhart/. Patients with venous and arterial thromoboembolic disorders are often treated with the anticoagulant coumarin derivative warfarin. Beside substantial improvements in oral anticoagulant therapy bleeding is still a dreaded complication. The risk of serious haemorrhage during warfarin therapy ranges from 1.3 to 4.2 % per 100 patient years of exposure (10). It is difficult to predict the optimal dose for warfarin therapy. The effective daily dose ranges from 0.5 mg to 60 mg (11). The cause for this interindividual variation in the response to a given dose of warfarin - ie the cause of hyper-responsiveness to small doses - lies in the genotype of the cytochrome P450 CYP2C9 (11-13). Aithal et al. (11) found that in a group of patients with a daily warfarin dose requirement of 1.5 mg or less 81 % had one or more of the variant alleles CYP2C9*2 or *3 present compared with 40 % in the control group. The genetically determined high-reponders to warfarin had bleeding complications four times more commonly than did a control group stabilised on larger doses of the drug (11). Genotyping of CYP2C9 identifys inidividuals who have an increased risk of bleeding complications. The initial doses of warfarin should be smaller for carriers of mutant alleles than the standard recommendation. Knowledge of the CYP2C9 genotype may also help the clinician to decide against the use of warfarin, particulary in high-risk elderly patients and choice other coumarin derivatives which are not influenced by CYP2C9 (11,14). In the pharmaceutical industry patients involved in clinical trials for the development of new drugs are already regulary genotyped in order to obtain informations about pharmacokinetic properties and observed side-effects (3). Informations about the genotype provide the doctor with predictive information of the likelihood of successful drug therapy and the possibility to individualize the drug dose of the specific patient (3). |
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| Literature (1) Glue P and Clement RP (1999) Cytochrome P450 Enzymes and Drug Metabolism - Basic Concepts and Methods of Assessment Cell Mol Neur 19: 309-324 (2) Lazarou J, Pomeranz BH and Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies JAMA 279: 1200-1205 (3) Ingelman-Sundberg M, Oscarson M and McLellan RA (1999) Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment TIPS, 20:342-349 (4) Wong L.-L. (1998) Cytochrome P450 monooxygenases Curr Opin Chem Biol 2: 263-268 (5) Bertz RJ and Granneman GR (1997) Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions Clin Pharmacokinet 32: 210-258 (6) Ibeanu GC, Goldstein JA, Meyer U ... (1998) Identification of New Human CYP2C19 Alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian Poor Metabolizer of Mephenytoin J Pharmacol Exp Ther 284: 356-361 (7) Goldstein JA, Ishizaki T, Chiba K ... (1997) Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations Pharmacogenetics 7: 59-64 (8) Coutts RT and Urichuk LJ (1999) Polymorphic Cytochromes P450 and Drugs Used in Psychiatry Cell Mol Neur 19: 325-354 (9) Andersson T, Holmberg J, Rohss K ... (1998) Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole Br J Clin Pharmacol 45: 369-375 (10) Furuta T, Ohashi K, Kamata T ... (1998) Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer Ann Intern Med 129: 1027-1030 (11) de Morais SMF, Wilkinson GR, Blaisdell J ... (1994) The Major Genetic Defect Responsible for the Polymorphism of S-Mephenytoin Metabolism in Humans JBC 269: 15419-15422 |
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