Prediction of the CYP2D6 enzymatic activity based on investigating of the CYP2D6 genotypes around the vivax malaria patients in Yunnan Province, China

Background In recent years, the incidence rate of vivax malaria recurrence still had 3.1% in Yunnan Province population after eradication therapy using primaquine (PQ). In order to understand the specific failure reasons for preventing vivax malaria relapses, a preliminary exploration on the CYP2D6 enzyme activity was carried out in the vivax malaria patients in Yunnan Province population by analysing mutational polymorphism in the coding region of CYP2D6 gene. Methods Blood samples were collected from vivax malaria patients with suspected relapse (SR) and non-relapsed (NR) malaria in Yunnan Province. The DNA fragments containing 9 exons regions of human CYP2D6 gene were amplified by performing PCR and sequenced. The sequencing results were aligned by using DNAStar 11.0 to obtain the coding DNA sequence (CDS) of CYP2D6 gene. DnaSP 6.11.01 software was used to identify mutant polymorphisms and haplotypes of the CDS chain. The waterfall function of GenVisR package in R was utilized to visualize the mutational landscape. The alleles of CYP2D6 gene were identified according to the criteria prescribed by Human Cytochrome P450 (CYP) Allele Nomenclature Committee Database and the CYP2D6 enzyme activity was predicted based on diploid genotype. Results A total of 320 maternal CDS chains, including 63 from SR group and 257 from NR group, were obtained. Twelve mutant loci, including c.31 (rs769259), c.100 (rs1065852), c.271 (rs28371703), c.281 (rs28371704), c.294 (rs28371705), c.297 (rs200269944), c.336 (rs1081003), c.408 (rs1058164), c.505 (rs5030865), c.801 (rs28371718), c.886 (rs16947), and c.1,457 (rs1135840) were observed on the 640 CDS chains (including 320 maternal and 320 paternal chains). The high-frequency mutation at rs1135840 (0.703) and low-frequency mutation, such as rs28371703, were detected only in the SR group. The frequency of mutant rs1058164 and rs1135840 were significantly increased in the SR group ($${x}^{2}$$ x 2 = 4.468, 5.889, P < 0.05), as opposed to the NR group. Of the 23 haplotypes (from Hap_1 to Hap_23), the nomenclatures of 11 allelic forms could be found: Hap_3 was non-mutant, Hap_2 accounted for the highest frequency (36.9%, 236/640), and Hap_9 had the most complex sequence structure, containing 7 loci mutations. Allele *10 was the most frequent among these genotypes (0.423). Among the allele *10 standard named genotypes, *1/*10, *1/*1 and *2/*10 were significantly more frequent in the NR group ($${x}^{2}$$ x 2 = 3.911, P < 0.05) and all showed uncompromised enzyme activity; the impaired genotype *10/*39 was more frequent in the SR group ($${x}^{2}$$ x 2 = 10.050, P < 0.05), and genotype *4/*4was detected only in the SR group. Conclusion In the patients receiving PQ dosage in Yunnan Province population, both rs1135840 single nucleotide polymorphism and *10 allele form was common in the CYP2D6 gene. Low-frequency mutation sites, such as rs28371703, were only presented in patients with vivax malaria relapse.

Personalized approach to the administration of haloperidol in patients with acute alcoholic hallucinatie (literature review)

To date, it is known that haloperidol is used to treat productive psychopathological symptoms in acute alcoholic hallucinosis, but its use is associated with a high risk of developing undesirable drug reactions (NLR). A number of isoenzymes of the cytochrome P-450 family take part in the metabolism of haloperidol. The biotransformation of haloperidol occurs with the participation of the CYP2D6 isoenzyme encoded by the gene of the same name. The CYP2D6 gene is highly polymorphic, and this polymorphism can lead to a change in the activity of the encoded isoenzyme. Changes in the rate of biotransformation of haloperidol may affect the profile of its effectiveness and safety. This review is aimed at analyzing the information accumulated in the literature on the role of genetic factors in the formation of an individual response to haloperidol therapy in patients with acute alcoholic hallucinosis.

Identification of CYP2D6 allelic mutations in a sub-set of Karachi population

CYP2D6 gene polymorphism is considered a main obstacle in the process of drug metabolism under clinical diseases that affect pharmacokinetics of ~25% of antidepressants and other drugs. Inter-individual variation occurs in the amount and functional activity of CYP2D6 enzyme produce undesirable side effects. The primary aim of current research is to evaluate gene and genotypic frequencies of CYP2D6 *1 extensive metabolizer, *4 poor metabolizer and *10 intermediate metabolizer allelic variants among depressed patients and compared with normal subjects and other populations. Human genomic DNA was isolated. Genotyping was performed by Polymerase chain reaction followed by restriction endonucleases digestion for variants analysis. The results indicated gene frequency of CYP2D6*1 was 59% (CI 49.6,68.3%) in normal subjects whereas, CYP2D6*4 was 13% (CI 3.7, 22.3%) and CYP2D6*10 was 54% (44.7, 63.3%) predominantly found in depressed patients. The results demonstrate pronounced association of CYP2D6 *4 and *10 allelic variants with patient’s drug response activity.

Identification of CYP2D6 allelic mutations in a sub-set of Karachi population

CYP2D6 gene polymorphism is considered a main obstacle in the process of drug metabolism under clinical diseases that affect pharmacokinetics of ~25% of antidepressants and other drugs. Inter-individual variation occurs in the amount and functional activity of CYP2D6 enzyme produce undesirable side effects. The primary aim of current research is to evaluate gene and genotypic frequencies of CYP2D6 *1 extensive metabolizer, *4 poor metabolizer and *10 intermediate metabolizer allelic variants among depressed patients and compared with normal subjects and other populations. Human genomic DNA was isolated. Genotyping was performed by Polymerase chain reaction followed by restriction endonucleases digestion for variants analysis. The results indicated gene frequency of CYP2D6*1 was 59% (CI 49.6,68.3%) in normal subjects whereas, CYP2D6*4 was 13% (CI 3.7, 22.3%) and CYP2D6*10 was 54% (44.7, 63.3%) predominantly found in depressed patients. The results demonstrate pronounced association of CYP2D6 *4 and *10 allelic variants with patient’s drug response activity.

The association of CYP2D6 gene polymorphisms in the full-length coding region with higher recurrence rate of vivax malaria in Yunnan Province, China

Background Accumulating evidence suggest that compromised CYP2D6 enzyme activity caused by gene mutation could contribute to primaquine failure for the radical cure of vivax malaria. The current study aims to preliminarily reveal the association between the recurrence of vivax malaria in Yunnan Province and CYP2D6 gene mutation by analysing polymorphisms in the entire coding region of human CYP2D6 gene. Methods Blood samples were collected from patients with vivax malaria, who received "chloroquine and 8-day course of primaquine therapy" in Yunnan Province. The suspected relapsed cases were determined by epidemiological approaches and gene sequence alignment. PCR was conducted to amplify the CYP2D6 gene in the human genome, and the amplified products were then sequenced to compare with the non-mutation “reference” sequence, so as to ensure correct sequencing results and to determine 9 exon regions. Subsequently, the DNA sequences of 9 exons were spliced into the coding DNA sequence (CDS), which, by default, is known as maternal CDS. The paternal CDS was obtained by adjusting the bases according to the sequencing peaks. The mutation loci, haplotypes (star alleles), genotypes and odds ratios (OR) of all the CDSs were analysed. Results Of the119 maternal CDS chains in total with 1491 bp in length, 12 mutation sites in the 238 maternal and paternal CDS chains were detected. The c.408G > C mutation was most frequently detected in both suspected relapsed group (SR) and non-relapsed group (NR), reaching 85.2% (75/88) and 76.0% (114/150), respectively. The c.886C > T mutation was most closely related to the recurrence of vivax malaria (OR = 2.167, 95% CI 1.104–4.252, P < 0.05). Among the 23 haplotypes (Hap_1 ~ Hap_23), Hap_3 was non-mutant, and the sequence structure of Hap_9 was the most complicated one. Five star alleles, including *1, *2, *4, *10 and *39, were confirmed by comparison, and CYP2D6*10 allele accounted for the largest percentage (45.4%, 108/238). The frequency of CYP2D6*2 allele in the SR group was significantly higher than that in the NR group (Χ2 = 16.177, P < 0.05). Of the defined 24 genotypes, 8 genotypes, including *4/*4, *4/*o, *2/*39, *39/*m, *39/*x, *1/*r, *1/*n, and *v/*10, were detected only in the SR group. Conclusion Mutation of CYP2D6*10 allele accounts for the highest proportion of vivax malaria cases in Yunnan Province. The mutations of c. 886C > T and CYP2D6*2 allele, which correspond to impaired PQ metabolizer phenotype, are most closely related to the relapse of vivax malaria. In addition, the genotype *4/*4 with null CYP2D6 enzyme function was only detected in the SR group. These results reveal the risk of defected CYP2D6 enzyme activity that diminishes the therapeutic effect of primaquine on vivax malaria.

Influence of CYP2D6 gene polymorphisms on the pharmacokinetics of aripiprazole in healthy Chinese subjects

Background: Pharmacogenetics study was added into 2 bioequivalence trials of aripiprazole. The correlation between CYP2D6 polymorphisms and aripiprazole pharmacokinetics (PK) was analyzed. Materials & methods: A total of 140 subjects were included. A total of 26 CYP2D6 gene alleles were detected. The plasma concentration of aripiprazole was measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS). SPSS Statistics 21 was used to analyze the correlation between CYP2D6 polymorphisms and aripiprazole PK parameters. Results: All of the four PK parameters were significantly influenced by CYP2D6 rs1058164 and rs28371699. t1/2 and area under the concentration-time curve (AUC0–∞) exhibited significant difference between CYP2D6 extensive metabolizers and intermediate metabolizers. Conclusion: Aripiprazole PK was greatly influenced by CYP2D6. Attention should be paid to the possible dose adjustment for CYP2D6 intermediate metabolizer population when the drug is used in Chinese patients.

Impact of CYP2D6 gene polymorphic marker G1846A carriage on the hemodynamic effect of propranolol in patients with liver cirrhosis

To evaluate the impact of CYP2D6 gene polymorphic marker G1846A carriage on the hemodynamic effect of propranolol in patients with liver cirrhosis.

MicroRNA hsa-miR-370-3p is a new biomarker for assessing the level of CYP2D6 gene expression, as well as the clinical efficacy and safety of mirtazapine in patients with depressive disorders comorbid with alcohol use disorder

Проведено изучение влияния полиморфизма гена CYP2D6 на эффективность и безопасность терапии миртазапина у пациентов с депрессивными расстройствами, коморбидными с алкоголизмом. В группе из 106 пациентов с депрессивными расстройствами, коморбидными с алкогольной зависимостью, было продемонстрировано влияние полиморфизма 1846G>A гена CYP2D6 (rs3892097) на показатели профиля безопасности миртазапина, но не эффективности. При этом hsa-miR-370-3p остается перспективным биомаркером оценки уровня экспресии гена CYP2D6, так как уровень его плазменной концентрации отличался у носителей разных генотипов по полиморфному маркеру 1846G>A, хотя и не обнаружилась связь с клинической эффективностью и безопасностью. The study of the effect of CYP2D6 gene polymorphism on the efficacy and safety of mirtazapine therapy in patients with depressive disorders comorbid with alcoholism was carried out. In a group of 106 patients with depressive disorders comorbid with alcohol dependence, the effect of the 1846G> A polymorphism of the CYP2D6 gene (rs3892097) on the safety profile of mirtazapine was demonstrated, but not on the effectiveness. At the same time, hsa-miR-370-3p remains a promising biomarker for assessing the level of CYP2D6 gene expression, since the level of its plasma concentration differed in carriers of different genotypes for the polymorphic marker 1846G> A, although no connection with clinical efficacy and safety was found.