Genetic polymorphism of CYP2D6

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

ABSTRACT 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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    ABSTRACT: The paper gives an overview on the allelic variant of CYP2D6 genotype. The gene CYP2D6*3 encodes a member of the cytochrome P 450 super family of enzymes. The cytochrome P 450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The protein localizes to the endoplasmic reticulum and is known to metabolize as many as 20% of commonly prescribed drugs. Its substrates include debrisoquine, an adrenergic-blocking drug; sparteine and propafenone, both anti-arrythmic drugs; and amitryptiline, an anti-depressant. The emerging application of pharmacogenomics in the clinical trials requires careful comparison with the traditional genotypic methodologies particularly in the drug metabolism area.
    AFRICAN JOURNAL OF BIOTECHNOLOGY 01/2011; 9:9096-9102. · 0.57 Impact Factor
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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.
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    ABSTRACT: The present study aimed as a first attempt on the North Indian population to establish the CYP2C19 phenotype frequencies among the population of Uttarakhand. A total of 20 physically healthy and unrelated human subjects of either sex (both male and female), with age range from 18-30 yrs, body weight ≥ 40 kg, participated in this study. After an overnight fast, each subject received a single dose of 20 mg omeprazole capsule orally. Blood samples (5ml) were collected just before (at 0 hr) and 3 hr after the drug administration. Plasma was separated after centrifugation and stored at -20ºC until analysis. The plasma concentrations of omeprazole and its metabolite, 5-hydroxyomeprazole, were determined by using High performance liquid chromatography (HPLC) method of analysis with some modifications. The metabolites were separated using a mixture of acetonitrile: 0.05 M phosphate buffer (20:80, ph 8.5) at flow rate of 1.5 ml/min. Metabolites were detected by their absorbance at 250 nm. Amounts were calculated from standard curves of omeprazole and its metabolite constructed in the concentration range of 10–1000 ng/ml. Out of 20 subjects, 17 (85%) were EMs and 03 (15%) were PMs. The prevalence of PMs in study population of Uttarakhand was found to be 15% by phenotyping, which is slightly greater than frequencies of South Indians (14%), Gujratis and Marwadis (10.32%), Southeast Asians like Thai (9.2%), Burmese (11%) and Karen (8.4%), Koreans (12.6%) and some other North Indians (10-12%). On the other hand, this PM frequency of 15% is found to be lower than the frequency found in Mexicans (31%), Japanese (27-35%). Our study population possesses 15% PMs, which is essential to evaluate the phenotype-genotypes correlation in this population after the genotyping data is available. It is now further suggested that future studies on genetic polymorphism on subjects of Uttarakhand be carried out on large study population for better interpretation and may involve the correlation of phenotype-genotype data along with observations that relate them to the findings such as adverse drug reaction monitoring, drug therapy decisions like cost and duration of therapy.
    International Journal of Advances in Pharmaceutical Sciences. 01/2010; 1:358-363.

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