RESUMO
Abstract Genetic variability in the host metabolism of antimalarial drugs influenced by the polymorphisms of cytochrome P450 (CYP) could lead to significant changes in antimalarial treatment response. However, little is known about the frequency of alleles CYP2B6, CYP2C8, and CYP2D6 in an Amazonian population, especially with vivax malaria. Therefore, this study aimed to determine the frequency of CYP alleles CYP2B6*6, CYP2C8*3, and CYP2D6*4 in patients with vivax malaria. The study included 231 patients with vivax malaria treated at a health care reference in Manaus, northern Brazil. A sample of peripheral blood from each subject was collected to perform DNA extraction and genotypic analysis. Genotyping of polymorphisms was performed by allelic discrimination using Real-time polymerase chain reaction. The CYP2D6*4 allele was the most prevalent among patients who developed severe malaria. The frequencies of the CYP2B6*6 and CYP2D6*4 were not different between the severe and uncomplicated malaria. There was a significant association between heterozygous CYP2D6*4 and severe cases of malaria. The results are in agreement with other reports described in the literature for different populations. Future studies are needed to understand the clinical implications of the polymorphisms in patients with vivax malaria.
Assuntos
Humanos , Masculino , Feminino , Pacientes/classificação , Polimorfismo Genético , Malária Vivax/patologia , Ecossistema Amazônico , Citocromo P-450 CYP2D6/efeitos adversos , Alelos , Citocromo P-450 CYP2B6/efeitos adversos , Citocromo P-450 CYP2C8/efeitos adversos , Antimaláricos/administração & dosagemRESUMO
Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the most important dose-limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random-effects gene meta-analyses and examined interstudy heterogeneity with meta-regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single-nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta-analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1-rs2032582, ABCB1-rs3213619, BCL6/-rs1903216, /CAND1-rs17781082, CYP1B1-rs1056836, CYP2C8-rs10509681, CYP2C8-rs11572080, EPHA5-rs7349683, EPHA6-rs301927, FZD3-rs7001034, GSTP1-rs1138272, TUBB2A-rs9501929, and XKR4-rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta-analysis. In conclusion, through systematic review and meta-analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.
Assuntos
Neoplasias da Mama , Síndromes Neurotóxicas , Doenças do Sistema Nervoso Periférico , Taxoides , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP3A/genética , Marcadores Genéticos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Síndromes Neurotóxicas/genética , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/complicações , Farmacogenética , Polimorfismo de Nucleotídeo Único , Taxoides/efeitos adversosRESUMO
PURPOSE: This study hypothesized that drugs accumulate in the bloodstream of poor-metabolizing patients and may have more adverse effects and different pain perceptions and aimed to investigate the influence of CYP450 polymorphisms on acute postoperative pain, swelling, and trismus controlled by ibuprofen (600 mg) in 200 volunteers after dental extraction. In addition, surgical outcomes can determine pain, edema, and trismus and indicate inflammatory reactions after oral surgeries. METHODS: Genetic sequencing was performed to identify CYP450 polymorphisms and the surgical parameters evaluated: pre and postoperative swelling, trismus, and temperature; self-reported postoperative pain with visual analog scale (VAS); rescue medication consumed; and severity of adverse reactions. RESULTS: A multiple linear regression model with independent variables [single nucleotide polymorphisms (SNPs), BMI (body mass index), duration, and difficulty of surgery] and dependent variables [postoperative pain by sum of pain intensity difference (SPID), trismus, and swelling] was used for analysis. The duration of surgery was a predictor for pain at 8 h and 96 h after surgery, and BMI was a predictor for both swelling and trismus on the 2nd postoperative day. When evaluating CYP2C8 and C9 genotyped SNPs, it was observed that normal metabolizers showed higher pain levels than the intermediate/poor metabolizers on the postoperative periods as compared with time 0 h. In another analysis, the poor metabolizers for CYP2C8 and C9 presented lower levels of postoperative pain after 8 h and used rescue medication earlier than normal metabolizers. CONCLUSION: Ibuprofen 600 mg was very effective in controlling inflammatory pain after lower third molar surgeries, without relevant adverse reactions; although in a very subtle way, patients with poor metabolism had higher levels of pain in the first hours, and no longer after 8 h, and used pain relief medication earlier. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov ID (NCT03169127), on March 16th, 2017.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Sistema Enzimático do Citocromo P-450/genética , Ibuprofeno/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Extração Dentária/efeitos adversos , Adolescente , Adulto , Índice de Massa Corporal , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C9/genética , Método Duplo-Cego , Edema/tratamento farmacológico , Edema/etiologia , Feminino , Humanos , Masculino , Dente Serotino/cirurgia , Duração da Cirurgia , Medição da Dor , Farmacogenética , Polimorfismo de Nucleotídeo Único , Trismo/tratamento farmacológico , Trismo/etiologia , Adulto JovemRESUMO
Cytochrome P450 (CYP) enzymes are involved in the biotransformation of chloroquine (CQ), but the role of the different profiles of metabolism of this drug in relation to Plasmodium vivax recurrences has not been properly investigated. To investigate the influence of the CYP genotypes associated with CQ metabolism on the rates of P. vivax early recurrences, a case-control study was carried out. The cases included patients presenting with an early recurrence (CQ-recurrent individuals), defined as a recurrence during the first 28 days after initial infection and plasma concentrations of CQ plus desethylchloroquine (DCQ; the major CQ metabolite) higher than 100 ng/ml. A control group with no parasite recurrence over the follow-up (the CQ-responsive group) was also included. CQ and DCQ plasma levels were measured on day 28. CQ-metabolizing CYP (CYP2C8, CYP3A4, and CYP3A5) genotypes were determined by real-time PCR. An ex vivo study was conducted to verify the efficacy of CQ and DCQ against P. vivax isolates. The frequency of alleles associated with normal and slow metabolism was similar between the cases and the controls for the CYP2C8 (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 0.51 to 4.14, P = 0.570), CYP3A4 (OR = 2.38, 95% CI = 0.92 to 6.19, P = 0.105), and CYP3A5 (OR = 4.17, 95% CI = 0.79 to 22.04, P = 1.038) genes. DCQ levels were higher than CQ levels, regardless of the genotype. Regarding the DCQ/CQ ratio, there was no difference between groups or between those patients who had a normal genotype and those patients who had a mutant genotype. DCQ and CQ showed similar efficacy ex vivo CYP genotypes had no influence on early recurrence rates. The similar efficacy of CQ and DCQ ex vivo could explain the absence of therapeutic failure, despite the presence of alleles associated with slow metabolism.
Assuntos
Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A , Malária Vivax , Estudos de Casos e Controles , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP3A/genética , Genótipo , Humanos , Malária Vivax/genética , Plasmodium vivax , RecidivaRESUMO
Aim: The influence of variants in pharmacokinetics-related genes on long-term exposure to tacrolimus (TAC)-based therapy and clinical outcomes was investigated. Patients & methods: Brazilian kidney recipients were treated with TAC combined with everolimus (n = 178) or mycophenolate sodium (n = 97). The variants in CYP2C8, CYP2J2, CYP3A4, CYP3A5, POR, ABCB1, ABCC2, ABCG2, SLCO1B1 and SLCO2B1 were analyzed. Main results:CYP3A5*3/*3 genotype influenced increase in TAC concentration from week 1 to month 6 post-transplantation (p < 0.05). The living donor and CYP2C8*3 variant were associated with reduced risk for delayed graft function (OR = 0.07; 95% CI = 0.03-0.18 and OR = 0.45; 95% CI = 0.20-0.99, respectively, p < 0.05). Conclusion: The CYP3A5*3 variant is associated with increased early exposure to TAC. Living donor and CYP2C8*3 variant seem to be protective factors for delayed graft function in kidney recipients.
Assuntos
Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP3A/genética , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Tacrolimo/efeitos adversos , Adulto , Brasil/epidemiologia , Feminino , Genótipo , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Polimorfismo de Nucleotídeo Único/genética , Tacrolimo/administração & dosagem , Tacrolimo/imunologia , Resultado do TratamentoRESUMO
STUDY OBJECTIVE: To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. DESIGN: Pharmacogenetic analysis of patients enrolled in a previously published study. PATIENTS: One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation. MEASUREMENTS AND MAIN RESULTS: ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05). CONCLUSION: The ABCC2 c.3972C >T polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.-76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.
Assuntos
Citocromo P-450 CYP2C8/genética , Sistema Enzimático do Citocromo P-450/genética , Rejeição de Enxerto/genética , Transplante de Rim , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Ácido Micofenólico/uso terapêutico , Tacrolimo/uso terapêutico , Adulto , Brasil/epidemiologia , Citocromo P-450 CYP2J2 , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Masculino , Proteína 2 Associada à Farmacorresistência Múltipla , Ácido Micofenólico/sangue , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Tacrolimo/sangue , Resultado do TratamentoRESUMO
Although Plasmodium vivax relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms are implicated in PQ failure, which was reinforced by findings in genetically similar parasites, and may explain a number of vivax relapses. Using a computational approach, these polymorphisms were predicted to affect the activity of CYP2D6 through changes in the structural stability that could lead to disruption of the PQ-enzyme interactions. Furthermore, because PQ is co-administered with chloroquine (CQ), we investigated whether CQ-impaired metabolism by cytochrome P-450 2C8 (CYP2C8) could also contribute to vivax recurrences. Our results show that CYP2C8-mutated patients frequently relapsed early (<42 days) and had a higher proportion of genetically similar parasites, suggesting the possibility of recrudescence due to CQ therapeutic failure. These results highlight the importance of pharmacogenetic studies as a tool to monitor the efficacy of antimalarial therapy.
Assuntos
Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Malária Vivax/tratamento farmacológico , Adolescente , Adulto , Antimaláricos/metabolismo , Antimaláricos/uso terapêutico , Criança , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2D6/genética , Feminino , Genótipo , Humanos , Malária Vivax/patologia , Masculino , Pessoa de Meia-Idade , Plasmodium vivax/enzimologia , Plasmodium vivax/genética , Polimorfismo de Nucleotídeo Único , Primaquina/metabolismo , Primaquina/uso terapêutico , Recidiva , Adulto JovemRESUMO
This study was designed to investigate the potential differences between Spaniards and Ecuadorian Mestizo people regarding CYP2C8, CYP2C9, and CYP2C19 genetic polymorphisms. DNA from 282 Spaniard and 297 Ecuadorian subjects were analyzed by either a previously reported pyrosequencing method (CY2C8*3, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3) or a nested PCR technique (CYP2C19*17). Whereas CYP2C19*17 allele distribution was higher in Ecuadorians than in Spaniards (P < 0.001) and the frequency of CYP2C19*3 was similar in these two populations (P > 0.05), the other allelic variants were detected at significantly lower frequencies in Ecuadorians than in Spaniards (P < 0.05). According to the diplotype distributions, the prevalence of the presumed CYP2C9 and CYP2C8 extensive metabolizers was higher in Ecuadorians than in Spaniards (P < 0.05). Individuals genotyped CYP2C19*1/*17 and *17/*17 who were considered as ultrarapid metabolizers were overrepresented in Ecuadorians in relation to Spaniards (P < 0.001). By contrast, among Ecuadorians no poor metabolizers (PMs) of either CYP2C8 or CYP2C9 were found and only two individuals were CYP2C19 PMs. These data are compatible with a higher CYP2C8, CYP2C9, and CYP2C19 activity in Mestizo Ecuadorians as opposed to Spaniards, which could imply differences in dosage requirements for drugs metabolized by these cytochromes and should also be considered in allele-disease association studies.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Genética Populacional , Adulto , Alelos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Equador , Feminino , Humanos , Inativação Metabólica/genética , Indígenas Sul-Americanos/genética , Masculino , Polimorfismo Genético , População Branca/genéticaRESUMO
AIM: Pharmacogenetic studies in breast cancer (BC) may predict the efficacy of tamoxifen and the toxicity of paclitaxel and capecitabine. We determined the frequency of polymorphisms in the CYP2D6 gene associated with activation of tamoxifen, and those of the genes CYP2C8, CYP3A5 and DPYD associated with toxicity of paclitaxel and capecitabine. We also included a IL-10 gene polymorphism associated with advanced tumor stage at diagnosis. PATIENTS & METHODS: Genomic DNAs from 241 BC patients from northeast Mexico were genotyped using DNA microarray technology. RESULTS: For tamoxifen processing, CYP2D6 genotyping predicted that 90.8% of patients were normal metabolizers, 4.2% ultrarapid, 2.1% intermediate and 2.9% poor metabolizers. For paclitaxel and the CYP2C8 gene, 75.3% were normal, 23.4% intermediate and 1.3% poor metabolizers. Regarding the DPYD gene, only one patient was a poor metabolizer. For the IL-10 gene, 47.1% were poor metabolizers. CONCLUSION: These results contribute valuable information towards personalizing BC chemotherapy in Mexican women.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Interleucina-10/genética , Polimorfismo Genético/genética , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina , Citocromo P-450 CYP2C8 , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Genótipo , Humanos , México , Pessoa de Meia-Idade , Paclitaxel/uso terapêutico , Espanha , Tamoxifeno/uso terapêuticoRESUMO
CYP2C8 is an important member of the cytochrome P450 family of enzymes; it affects the activity of various drugs used in routine clinical practice, including amiodarone, chloroquine, amodiaquine, and repaglinide, as well as endogenous compounds, such as arachidonic acid and retonic acid. It is also the main enzyme involved in the metabolism of the widely used anticancer drug Paclitaxel, which has a very narrow therapeutic index. There is evidence that single nucleotide polymorphisms in the CYP2C8 gene influence the adverse reactions and/or the efficacy of drugs metabolized by this enzyme. We examined the allele and genotype frequencies of widely studied functional polymorphisms of the CYP2C8 gene in a North Indian population. We assayed the genomic DNA of at least 251 healthy unrelated North Indians for CYP2C8*2, CYP2C8*3 (G416A, A1196G), and CYP2C8*4 genetic polymorphisms by RFLP technique. These results were compared to information on other populations. The allelic frequencies of CYP2C8*2, CYP2C8*3, and CYP2C8*4 were found to be 3, 4, and 4% respectively. The two CYP2C8*3 polymorphisms (G416A and A1196G) were found to be completely linked to each other. Allele frequencies of CYP2C8 genetic variants in northern Indians were found to have a distinct pattern that differs from that of southern Indian and other global populations. This is the first report from North India on CYP2C8 polymorphisms. Ethnic differences with respect to polymorphisms are the molecular basis of interethnic variability in pharmacokinetics. Our study may help in rational use of drugs that are substrates for CYP2C8 in this population.