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      Distribution of CYP2B6 516G/T pharmacogenetically important polymorphism in the Ukrainian population

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          Abstract

          The CYP2B6 is one of the members of the cytochrome P450 superfamily. This enzyme metabolizes a number of currently prescribed drugs and different compounds. In light of clinical significance of the CYP2B6∗6 variant of the CYP2B6 gene, the aim of this study was to investigate the distribution of one of the gene polymorphisms, namely, the 516G/T in the Ukrainian population.

          The study cohort consisted of 102 healthy Ukrainian adults (48 males, 54 females). Genotyping of the CYP2B6 (rs3745274) polymorphism in the study subjects was carried out using a polymerase chain reaction.

          The following distribution of 516G/T CYP2B6 genotypes in the Ukrainian cohort was identified: GG – in 56%, GT – in 37% and TT – in 7%. The 516G/T allele frequency of the CYP2B6 gene in population was p G = 0.75 and q T = 0.25, respectively. The population-based sequences were analyzed by the Hardy-Weinberg method.

          The genetic polymorphism revealed in the Ukrainian population suggests the 516G/T polymorphism of the CYP2B6 genetic testing when prescribing the drugs that are substrates of this gene.

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          Most cited references13

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          Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material.

          Procedures utilizing Chelex 100 chelating resin have been developed for extracting DNA from forensic-type samples for use with the PCR. The procedures are simple, rapid, involve no organic solvents and do not require multiple tube transfers for most types of samples. The extraction of DNA from semen and very small bloodstains using Chelex 100 is as efficient or more efficient than using proteinase K and phenol-chloroform extraction. DNA extracted from bloodstains seems less prone to contain PCR inhibitors when prepared by this method. The Chelex method has been used with amplification and typing at the HLA DQ alpha locus to obtain the DQ alpha genotypes of many different types of samples, including whole blood, bloodstains, seminal stains, buccal swabs, hair and post-coital samples. The results of a concordance study are presented in which the DQ alpha genotypes of 84 samples prepared using Chelex or using conventional phenol-chloroform extraction are compared. The genotypes obtained using the two different extraction methods were identical for all samples tested.
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            Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes.

            Nicotine C-oxidation by recombinant human cytochrome P450 (P450 or CYP) enzymes and by human liver microsomes was investigated using a convenient high-performance liquid chromatographic method. Experiments with recombinant human P450 enzymes in baculovirus systems, which co-express human nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH)-P450 reductase, revealed that CYP2A6 had the highest nicotine C-oxidation activities followed by CYP2B6 and CYP2D6; the Km values by these three P450 enzymes were determined to be 11.0, 105, and 132 microM, respectively, and the Vmax values to be 11.0, 8.2, and 8.6 nmol/min per nmol P450, respectively. CYP2E1, 2C19, 1A2, 2C8, 3A4, 2C9, and 1A1 catalysed nicotine C-oxidation only at high (500 microM) substrate concentration. CYP1B1, 2C18, 3A5, and 4A11 had no measurable activities even at 500 microM nicotine. In liver microsomes of 16 human samples, nicotine C-oxidation activities were correlated with CYP2A6 contents at 10 microM substrate concentration, whereas such correlation coefficients were decreased when the substrate concentration was increased to 500 microM. Contribution of CYP2B6 (as well as CYP2A6) was demonstrated by experiments with the effects of orphenadrine (and also coumarin and anti-CYP2A6) on the nicotine C-oxidation activities by human liver microsomes at 500 microM nicotine. CYP2D6 was found to have minor roles since quinidine did not inhibit microsomal nicotine C-oxidation at both 10 and 500 microM substrate concentrations. These results support the view that CYP2A6 has major roles for nicotine C-oxidation at lower substrate concentration and both CYP2A6 and 2B6 play roles at higher substrate concentrations in human liver microsomes.
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              CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction.

              Adequate methadone dosing in methadone maintenance treatment (MMT) for opioid addiction is critical for therapeutic success. One of the challenges in dose determination is the inter-individual variability in dose-response. Methadone metabolism is attributed primarily to cytochrome P450 enzymes CYP3A4, CYP2B6 and CYP2D6. The CYP2B6*6 allele [single nucleotide polymorphisms (SNPs) 785A>G (rs2279343) and 516G>T (rs3745274)] was associated with slow methadone metabolism. To explore the effects of CYP2B6*6 allele on methadone dose requirement, it was genotyped in a well-characterized sample of 74 Israeli former heroin addicts in MMT. The sample is primarily of Middle Eastern/European ancestry, based on ancestry informative markers (AIMs). Only patients with no major co-medication that may affect methadone metabolism were included. The stabilizing daily methadone dose in this sample ranges between 13 and 260mg (mean 140±52mg). The mean methadone doses required by subjects homozygous for the variant alleles of the CYP2B6 SNPs 785A>G and 516G>T (88, 96mg, respectively) were significantly lower than those of the heterozygotes (133, 129mg, respectively) and the non-carriers (150, 151mg, respectively) (nominal P=0.012, 0.048, respectively). The results remain significant after controlling for age, sex and the ABCB1 SNP 1236C>T (rs1128503), which was previously shown to be associated with high methadone dose requirement in this population (P=0.006, 0.030, respectively). An additional 77 CYP2B6, CYP3A4 and CYP2D6 SNPs were genotyped. Of these, 24 SNPs were polymorphic and none showed significant association with methadone dose. Further studies are necessary to replicate these preliminary findings in additional subjects and other populations.
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                Author and article information

                Contributors
                Journal
                Saudi Pharm J
                Saudi Pharm J
                Saudi Pharmaceutical Journal : SPJ
                Elsevier
                1319-0164
                2213-7475
                15 February 2018
                July 2018
                15 February 2018
                : 26
                : 5
                : 651-655
                Affiliations
                [a ]Biology Department, National University of Pharmacy, Pushkinska Street, 53, Kharkov 61002, Ukraine
                [b ]Pharmaceutical Marketing and Management Department, National University of Pharmacy, Pushkinska Street, 53, Kharkov 61002, Ukraine
                [c ]Pharmacology Department, National University of Pharmacy, Pushkinska Street, 53, Kharkov 61002, Ukraine
                [d ]Pharmacognosy Department, National University of Pharmacy, Pushkinska Street, 53, Kharkov 61002, Ukraine
                Author notes
                [* ]Corresponding author. biology@ 123456nuph.edu.ua
                Article
                S1319-0164(18)30051-3
                10.1016/j.jsps.2018.02.027
                6035515
                29991909
                c0f6a0ea-5d9c-4c5b-9742-30d73884fe97
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 5 December 2017
                : 13 February 2018
                Categories
                Article

                cyp2b6 (516g/t) polymorphism,ukraine,population
                cyp2b6 (516g/t) polymorphism, ukraine, population

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