Genetic polymorphism of CYP2D6

Indian Journal of Pharmacology 01/2001; 33(3):147-169.


CYP2D6 is polymorphically distributed and is responsible for the metabolism of several clinically important drugs. It is also related to several pathophysiological conditions. Defect alleles, causing poor metaboliser (PM) phenotype and alleles with duplicated or multiduplicated active genes, causing ultra extensive metabolism (UEM) have been described. CYP2D6 polymorphism exhibits pronounced interethnic variation. While initial observation and studies focused on population of Caucasian origin, later other populations also studied extensively. Differences in metabolism of drugs can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of pharmacologically active drug or metabolite. Knowledge of individual's CYP2D6 status may be clinically and economically important and could provide the basis for a rational approach to drug prescription. Genetic polymorphism CYP2D6 pharmacogenetics KEY WORDS CYP 'CYP' is the abbreviation for cytochrome P-450, a subgroup of related enzymes or isoenzymes located in the endoplasmic reticulum and expressed mainly in the liver. It is also present in other organs, such as the intestine and the brain 4 . In mammals, most xenobiotics are metabolised via hepatic phase 1 metabolism by means of CYP monooxygenases 5 . Thirty or more different forms of these haem thiolate proteins have been characterized in humans 3 . The P450 superfamily is composed of families and sub-families of enzyme that are defined solely on the basis of their amino acid sequence similarities. With few exceptions, a P450 protein sequence from one fam-ily exhibits upto 40% resemblance to a P450 from other family. P450s with in a single subfamily always share greater than 55% sequence similarity 6,7 .

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    • "Cytochrome P450 (CYP2D6) group of enzymes is the most widely studied since they metabolize majority of drugs used in clinical practice. CYP2D62D6 metabolizes approximately 25% of drugs[12] such as selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, beta-blockers, and histamine receptor blockers.[3] Genotyping studies of CYP2D6 performed worldwide have shown a wide array of mutant alleles (from *1 to *41) with prevalence ranging from 0% to 8.4%, respectively.[34] "
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    ABSTRACT: Background: Cytochrome P450 2D6 (CYP2D6) metabolizes around 25% of the drugs used in therapeutics and different polymorphisms have been identified in various populations. This study aimed at finding the prevalence of CYP2D6 polymorphisms using dextromethorphan as a probe drug. Materials and Methods: Healthy participants were administered 60 mg dextromethorphan after an overnight fast and 5 ml of blood was collected 3 h postdose. A validated laboratory method was used to measure both dextromethorphan and its active metabolite, dextrorphan from plasma. Metabolic ratio (MR) of dextromethorphan to dextrorphan was calculated for each of the participants. Probit analysis was done and antimode was defined. Individuals with log MR equal to or higher than the antimode were classified as poor metabolizers (PMs) and those with values less than antimode were categorized as extensive metabolizers (EMs). Results: Data from a total of 149 participants were evaluated and the median (range) of MR was 0.25 (0.03-3.01). The polynomial equation obtained in probit analysis gave an antimode for MR of 1.39. Five (3.36%) participants were PMs and 144 (96.64%) were found to be EMs. One participant had reported mild drowsiness 2 h postdose that subsided spontaneously without any intervention. Conclusion: The prevalence of CYP2D6 polymorphism in Western Indian population is low (3.36%) and is similar to other populations.
    Full-text · Article · May 2014 · Indian Journal of Pharmacology
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    • "rhythmics, and opioids) are typical substrates for CYP2D6. CYP2D6 is also responsible for the metaboo lism of known carcinogens, including nitrosamines, and probably nicotine (Abraham, Adithan, 2001). The activity of this enzyme can strongly vary in different individuals. "
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    ABSTRACT: The CYP2D6, GSTM1, and GSTT1 xenobiotic biotransformation genes are involved in processes of carcinogenesis in humans due to the presence of mutant variants that decrease or block the expression of genes. Since the middle of the 20th century, there has been an extensive increase in cancer morbidity in human populations, including indigenous ethnic groups of Siberia. The problem of ethnic differences in susceptibility to cancer is still pressing. The study of polymorphisms of the CYP2D6 (CYP2D6*3 and CYP2D6*4 alleles), GSTM1, and GSTT1 (GSTM1 0/0 and GSTT1 0/0 “null” genotypes) genes (which are considered as genetic markers of the risk of cancer) was conducted for the first time in practically healthy representatives of the Samoyedic ethnic groups (Selkups, Forest Nenets, and Nganasans) and Russians from Siberia. A significant variability in the CYP2D6*4 and GSTM1 0/0 frequency distribution in northern populations was detected. At the same time, there are no significant differences in frequencies of the CYP2D6*3 and GSTT1 0/0 variants among indigenous populations of the Selkups, Forest Nenets, and Nganasans. In the CYP2D6*4 allele frequencies, indigenous ethnic groups are intermediate between Russians of Siberia and Mongolians of China. However, frequencies of the null GSTM1 0/0 and GSTT1 0/0 genotypes in indigenous ethnic groups are significantly lower than in populations of Russians of Siberia and Mongoloids of China (p < 0.05). Generally, according to all four studied polymorphic variants, it is possible to predict a decreased risk of cancer in indigenous Samoyedic ethnic groups, as compared with Russians of Siberia. The Forest Nenets population, with an increased frequency of the GSTM1 0/0 genotypes, is an exception; this can be caused by the originality of their marriage structure and increased inbreeding coefficient. The results we obtained can also be important in predicting the probability of complications and a positive response to drugs that are metabolized by the GSTM1, GSTT1, and CYP2D6 enzymes.
    Full-text · Article · Feb 2012 · Russian Journal of Genetics: Applied Research
    • "With in vitro methods, it can be identified during preclinical studies, if the drug is metabolized by polymorphic enzymes,[19] and a decision regarding continuation of the trial can be made. Also, this information can help in selecting appropriate patients with normal metabolizing enzymes in phase I clinical trial; it can also help prevent adverse events.[20] It must be noted that pharmacogenetic principles can be used for inclusion or exclusion criteria only when the metabolic pathway of the drug is known. "
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    ABSTRACT: Pharmacogenetics and pharmacogenomics are two major emerging trends in medical sciences, which influence the success of drug development and therapeutics. In current times, though pharmacogenetic studies are being done extensively for research, its application for drug development needs to get started on a large scale. The major determinants of success of a new drug compound, viz safety and efficacy, have become more predictable, with the advent of pharmacogenetic studies. There is a need felt for pharmacogenomic studies, where the effects of multiple genes are assessed with the study of entire genome. Pharmacogenetic studies can be used at various stages of drug development. The effect of drug target polymorphisms on drug response can be assessed and identified. In clinical studies, pharmacogenetic tests can be used for stratification of patients based on their genotype, which corresponds to their metabolizing capacity. This prevents the occurrence of severe adverse drug reactions and helps in better outcome of clinical trials. This can also reduce attrition of drug compounds. Further, the variations in drug response can be better studied with the wider application of pharmacogenomic methods like genome wide scans, haplotype analysis and candidate gene approaches. The cost of pharmacogenetic testing has become very low, with the advent of newer high throughput genotyping systems. However, the cost of pharmacogenomic methods continues to be very high. As the treatment with several drugs is being more and more pharmacogeneticaly guided (e.g. warfarin and irinotecan), the FDA has laid down guidelines for pharmaceutical firms regarding submission of pharmacogenetic data for their drug products in labelling.
    No preview · Article · Aug 2008 · Indian Journal of Pharmacology
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