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1.
Plant Physiol Biochem ; 159: 226-233, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33387851

RESUMO

Plants can reduce or eliminate the damage caused by herbicides and gain herbicide resistance, which is an important theoretical basis for the development of herbicide-resistant crops at this stage. Thus, discovering novel herbicide-resistant genes to produce diverse herbicide-resistant crop species is of great value. The glycosyltransferases that commonly exist in plant kingdom modify the receptor molecules to change their physical characteristics and biological activities, and thus possess an important potential to be used in the herbicide-resistance breeding. Here, we identified a novel herbicide-induced UDP-glycosyltransferase 91C1 (UGT91C1) from Arabidopsis thaliana and demonstrated its glucosylating activity toward sulcotrione, a kind of triketone herbicides widely used in the world. Overexpression of UGT91C1 gene enhanced the Arabidopsis tolerance to sulcotrione. While, ugt91c1 mutant displayed serious damage and reduced chlorophyll contents in the presence of sulcotrione, suggesting an important role of UGT91C1 in herbicide detoxification through glycosylation. Moreover, it was also noted that UGT91C1 can affect tyrosine metabolism by reducing the sulcotrione toxicity. Together, our identification of glycosyltransferase UGT91C1, as a potential gene conferring herbicide detoxification through glucosylation, may open up a new possibility for herbicide resistant breeding of crop plants and environmental phytoremediation.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis , Glicosiltransferases/metabolismo , Resistência a Herbicidas , Inativação Metabólica , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Glicosiltransferases/genética , Resistência a Herbicidas/genética , Herbicidas/metabolismo , Herbicidas/toxicidade , Inativação Metabólica/genética
2.
PLoS One ; 16(1): e0243992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33428654

RESUMO

Insecticide resistance is a worldwide threat for vector control around the world, and Aedes aegypti, the main vector of several arboviruses, is a particular concern. To better understand the mechanisms of resistance, four isofemale strains originally from French Guiana were isolated and analysed using combined approaches. The activity of detoxification enzymes involved in insecticide resistance was assayed, and mutations located at positions 1016 and 1534 of the sodium voltage-gated channel gene, which have been associated with pyrethroid resistance in Aedes aegypti populations in Latin America, were monitored. Resistance to other insecticide families (organophosphates and carbamates) was evaluated. A large-scale proteomic analysis was performed to identify proteins involved in insecticide resistance. Our results revealed a metabolic resistance and resistance associated with a mutation of the sodium voltage-gated channel gene at position 1016. Metabolic resistance was mediated through an increase of esterase activity in most strains but also through the shifts in the abundance of several cytochrome P450 (CYP450s). Overall, resistance to deltamethrin was linked in the isofemale strains to resistance to other class of insecticides, suggesting that cross- and multiple resistance occur through selection of mechanisms of metabolic resistance. These results give some insights into resistance to deltamethrin and into multiple resistance phenomena in populations of Ae. aegypti.


Assuntos
Aedes/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Proteínas de Insetos/genética , Resistência a Inseticidas/genética , Canais de Sódio Disparados por Voltagem/genética , Aedes/efeitos dos fármacos , Aedes/genética , Animais , Esterases/metabolismo , Feminino , Guiana Francesa , Técnicas de Silenciamento de Genes , Genótipo , Inativação Metabólica/genética , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/metabolismo , Inseticidas/farmacologia , Mucosa Intestinal/metabolismo , Nitrilos/farmacologia , Oligonucleotídeos/metabolismo , Polimorfismo de Nucleotídeo Único , Proteoma/análise , Proteômica , Piretrinas/farmacologia , Canais de Sódio Disparados por Voltagem/química , Canais de Sódio Disparados por Voltagem/metabolismo
3.
Int J Biol Macromol ; 171: 150-157, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33418039

RESUMO

The cytochrome P450 monooxygenases of insects play crucial roles in the metabolic detoxification of insecticides. Our previous finding showed that two cytochrome P450 genes, both CYP301B1 and CYP6AX1v2, in the BPH underwent overexpression due to ß-asarone. In this study, we investigated the molecular characteristics, expression patterns and functions of these two cytochrome P450 genes. The results showed that CYP301B1 had the highest expression level in the eggs, while CYP6AX1v2 was expressed in macropterous female adults. Moreover, the expression level of CYP301B1 in the head was higher than that in the integument, fat body and gut. The expression level of CYP6AX1v2 in the fat body and gut was higher than that in head and integument. Importantly, silencing CYP301B1 and CYP6AX1v2 separately could increase the sensitivity, resulting in significant higher mortality of BPH following treatment with ß-asarone. Our findings indicated that CYP301B1 and CYP6AX1v2 could contribute to the resistance of BPH to ß-asarone, and these two genes may be involved in the detoxification metabolism of ß-asarone in BPH.


Assuntos
Anisóis/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Hemípteros/efeitos dos fármacos , Inativação Metabólica/genética , Proteínas de Insetos/genética , Inseticidas/farmacologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Sistema Enzimático do Citocromo P-450/metabolismo , Corpo Adiposo/efeitos dos fármacos , Corpo Adiposo/enzimologia , Regulação da Expressão Gênica , Cabeça , Hemípteros/enzimologia , Hemípteros/genética , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Zigoto/efeitos dos fármacos , Zigoto/enzimologia
4.
PLoS One ; 15(5): e0230950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365122

RESUMO

A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a pharmacogenomics-based pathway that standardizes and visualizes the components (nodes) and actions (edges) involved in pharmacokinetic and pharmacodynamic processes. It provides an intuitive understanding of the drug response in the human body. A pharmacokinetic pathway visualizes the absorption, distribution, metabolism, and excretion (ADME) at the systemic level, and a pharmacodynamic pathway shows the action of the drug in the target cell at the cellular-molecular level. The genes in the pathway are displayed in locations similar to those inside the body. PG-path allows personalized pathways to be created by annotating each gene with the overall impact degree of deleterious variants in the gene. These personalized pathways play a role in assisting tailored individual prescriptions by predicting changes in the drug concentration in the plasma. PG-path also supports counseling for personalized drug therapy by providing visualization and documentation.


Assuntos
Biologia Computacional/métodos , Redes e Vias Metabólicas/genética , Preparações Farmacêuticas/metabolismo , Farmacogenética/métodos , Medicina de Precisão/métodos , Software , Bases de Dados Genéticas , Tratamento Farmacológico/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Absorção Gastrointestinal/genética , Estudos de Associação Genética , Humanos , Inativação Metabólica/efeitos dos fármacos , Inativação Metabólica/genética , Armazenamento e Recuperação da Informação/métodos , Redes e Vias Metabólicas/efeitos dos fármacos , Modelos Teóricos
5.
Bull Entomol Res ; 110(6): 743-755, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32419680

RESUMO

Panonychus citri (McGregor) is the most common pest in citrus-producing regions. Special low-toxicity acaricides, such as spirocyclic tetronic acids and mite growth inhibitors, have been used for a long time in China. However, pesticide resistance in mites is a growing problem due to the lack of new acaricide development. Wide-spectrum insecticides, such as amitraz have gained acceptance among fruit growers. An amitraz-resistant strain of P. citri was obtained by indoor screening to examine field resistance monitoring of mites to acaricides and to explore the resistant mechanism of mites against amitraz. The amitraz-resistant strain of P. citri had an LC50 value of 2361.45 mg l-1. The resistance ratio was 81.35 times higher in the resistant strain of P. citri compared with the sensitive strain. Crossing experiments between the sensitive and resistant strains of P. citri were conducted, resulting in a D value of 0.11 for F1 SS♀×RS♂ and 0.06 for F1 RS♀×SS♂. Reciprocal cross experiments showed that the dose-mortality curves for the F1 generations coincided, indicating that the resistance trait was not affected by cytoplasmic inheritance. The dose-expected response relationship was evaluated in the backcross generation and a significant difference was observed compared with the actual value. The above results indicate that the inheritance of resistance trait was incompletely dominant, governed by polygenes on the chromosome. Synergism studies demonstrated that cytochrome P450s and esterase may play important roles in the detoxification of amitraz. Based on differential gene analysis, 23 metabolism-related genes of P. citri were identified, consistent with the results of synergism studies. Real-time PCR verification implied that P450s, ABC transporters, and acetylcholinesterase might influence the detoxification of amitraz by P. citri. These results provide the genetic and molecular foundation for the management of pest mite resistance.


Assuntos
Inativação Metabólica/genética , Tetranychidae/genética , Tetranychidae/metabolismo , Toluidinas , Acaricidas , Animais , Sistema Enzimático do Citocromo P-450 , Esterases , Tetranychidae/enzimologia
6.
Arch Insect Biochem Physiol ; 104(2): e21674, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32281173

RESUMO

Insects have evolved resistance to almost all insecticides developed for their control. Multiple mechanisms of resistance, including enhanced metabolism and excretion of insecticides, target-site insensitivity, reduced penetration of insecticides, and avoidance behavior, have been reported. The genes coding for proteins involved in resistance have been identified in numerous insects. The enzymes and transporters required for all three phases of insecticide metabolism and excretion including cytochrome P450 monooxygenases, glutathione S-transferases, UDP-glucuronosyltransferases, carboxylesterases, and ATP-binding cassette transmembrane transporters have been identified. Recent research in multiple insect species identified CNC-bZIP transcription factor superfamily members as regulators of genes coding for enzymes and transporters involved in insecticide metabolic resistance. The information on the pathway including reactive oxygen species, cap "n" collar isoform-C, and its heterodimer partner, muscle aponeurosis fibromatosis transcription factors involved in overexpression of enzymes and transporters involved insecticide resistance will be summarized.


Assuntos
Inativação Metabólica/genética , Proteínas de Insetos/genética , Insetos/efeitos dos fármacos , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Proteína Oncogênica v-maf/genética , Fatores de Transcrição/genética , Animais , Proteínas de Insetos/metabolismo , Insetos/genética , Proteína Oncogênica v-maf/metabolismo , Fatores de Transcrição/metabolismo
7.
Soft Matter ; 16(11): 2725-2735, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32115597

RESUMO

Transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) (PI-b-PEG) polymersomes were investigated for their potential use in the detoxification of ammonia, a metabolite that is excessively present in patients suffering from urea cycle disorders and advanced liver diseases, and which causes neurotoxic effects (e.g., hepatic encephalopathy). Polymers varying in PI and PEG block length were synthesized via nitroxide-mediated polymerization and screened for their ability to self-assemble into polymersomes in aqueous media. Ammonia sequestration by the polymersomes was investigated in vitro. While most vesicular systems were able to capture ammonia in simulated intestinal fluids, uptake was lost in partially dehydrated medium mimicking conditions in the colon. Polymeric crosslinking of residual olefinic bonds in the PI block increased polymersome stability, partially preserving the ammonia capture capacity in the simulated colon environment. These more stable vesicular systems hold promise for the chronic oral treatment of hyperammonemia.


Assuntos
Amônia/química , Portadores de Fármacos/química , Encefalopatia Hepática/tratamento farmacológico , Inativação Metabólica/genética , Amônia/metabolismo , Butadienos/química , Butadienos/farmacologia , Portadores de Fármacos/farmacologia , Fluoresceína-5-Isotiocianato/química , Hemiterpenos/química , Hemiterpenos/farmacologia , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Hepatopatias/complicações , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Metacrilatos/química , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Polimerização , Polímeros/química , Polímeros/farmacologia , Força Próton-Motriz/efeitos dos fármacos , Distúrbios Congênitos do Ciclo da Ureia/complicações , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Água/metabolismo
8.
Am J Physiol Cell Physiol ; 318(5): C889-C902, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159360

RESUMO

Approximately 75% of xenobiotics are primarily eliminated through metabolism; thus the accurate scaling of metabolic clearance is vital to successful drug development. Yet, when data is scaled from in vitro to in vivo, hepatic metabolic clearance, the primary source of metabolism, is still commonly underpredicted. Over the past decades, with biophysics used as a key component to restore aspects of the in vivo environment, several new cell culture settings have been investigated to improve hepatocyte functionalities. Most of these studies have focused on shear stress, i.e., flow mediated by a pressure gradient. One potential conclusion of these studies is that hepatocytes are naturally "mechanosensitive," i.e., they respond to a change in their biophysical environment. We demonstrate that hepatocytes also respond to an increase in hydrostatic pressure that, we suggest, is directly linked to the lobule geometry and vessel density. Furthermore, we demonstrate that hydrostatic pressure improves albumin production and increases cytochrome P-450 (CYP) 1A2 expression levels in an aryl hydrocarbon-dependent manner in human hepatocytes. Increased albumin production and CYP function are commonly attributed to the impacts of shear stress in microfluidic experiments. Therefore, our results highlight evidence of a novel link between hydrostatic pressure and CYP metabolism and demonstrate that the spectrum of hepatocyte mechanosensitivity might be larger than previously thought.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Citocromo P-450 CYP1A2/genética , Fígado/metabolismo , Mecanotransdução Celular/genética , Receptores de Hidrocarboneto Arílico/genética , Técnicas de Cultura de Células , Regulação da Expressão Gênica/genética , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Pressão Hidrostática , Inativação Metabólica/genética , Fígado/efeitos dos fármacos , Transdução de Sinais/genética
9.
Aquat Toxicol ; 222: 105462, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32169740

RESUMO

The copepod Tigriopus japonicus has been widely used as an experimental species in the field of ecotoxicology. We have sequenced and assembled the whole genome of T. japonicus with comparative analysis of gene families that represent detoxification phases in two additional public genomes of Tigriopus spp., namely, T. californicus and T. kingsejongensis. The total length of the T. japonicus assembled genome was 196.6 Mb with an N50 value of 10.65 Mb and consisted of 339 scaffolds and 25,143 annotated genes. The detoxification gene families encoding cytochrome P450s (CYP450s), glutathione S-transferases (GSTs), and ATP-binding cassette (ABC) proteins in Tigriopus spp. have shown species-dependent diversity in several gene sets, suggesting that these genes have undergone a species-specific expansion to increase their fitness to different marine habitats and environmental pressures. Our study will provide a better understanding of the detoxification system in Tigriopus spp. and will contribute to various areas of research, including ecotoxicology.


Assuntos
Copépodes/genética , Ecotoxicologia/métodos , Monitoramento Ambiental/métodos , Genoma , Poluentes Químicos da Água/toxicidade , Animais , Copépodes/efeitos dos fármacos , Copépodes/enzimologia , Sistema Enzimático do Citocromo P-450/genética , Ecossistema , Genômica , Glutationa Transferase/genética , Inativação Metabólica/genética , Anotação de Sequência Molecular , Especificidade da Espécie
10.
BMC Genomics ; 21(1): 120, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013879

RESUMO

BACKGROUND: Fluralaner is a novel isoxazoline insecticide with a unique action site on the γ-aminobutyric acid receptor (GABAR), shows excellent activity on agricultural pests including the common cutworm Spodoptera litura, and significantly influences the development and fecundity of S. litura at either lethal or sublethal doses. Herein, Illumina HiSeq Xten (IHX) platform was used to explore the transcriptome of S. litura and to identify genes responding to fluralaner exposure. RESULTS: A total of 16,572 genes, including 451 newly identified genes, were observed in the S. litura transcriptome and annotated according to the COG, GO, KEGG and NR databases. These genes included 156 detoxification enzyme genes [107 cytochrome P450 enzymes (P450s), 30 glutathione S-transferases (GSTs) and 19 carboxylesterases (CarEs)] and 24 insecticide-targeted genes [5 ionotropic GABARs, 1 glutamate-gated chloride channel (GluCl), 2 voltage-gated sodium channels (VGSCs), 13 nicotinic acetylcholine receptors (nAChRs), 2 acetylcholinesterases (AChEs) and 1 ryanodine receptor (RyR)]. There were 3275 and 2491 differentially expressed genes (DEGs) in S. litura treated with LC30 or LC50 concentrations of fluralaner, respectively. Among the DEGs, 20 related to detoxification [16 P450s, 1 GST and 3 CarEs] and 5 were growth-related genes (1 chitin and 4 juvenile hormone synthesis genes). For 26 randomly selected DEGs, real-time quantitative PCR (RT-qPCR) results showed that the relative expression levels of genes encoding several P450s, GSTs, heat shock protein (HSP) 68, vacuolar protein sorting-associated protein 13 (VPSAP13), sodium-coupled monocarboxylate transporter 1 (SCMT1), pupal cuticle protein (PCP), protein takeout (PT) and low density lipoprotein receptor adapter protein 1-B (LDLRAP1-B) were significantly up-regulated. Conversely, genes encoding esterase, sulfotransferase 1C4, proton-coupled folate transporter, chitinase 10, gelsolin-related protein of 125 kDa (GRP), fibroin heavy chain (FHC), fatty acid synthase and some P450s were significantly down-regulated in response to fluralaner. CONCLUSIONS: The transcriptome in this study provides more effective resources for the further study of S. litura whilst the DEGs identified sheds further light on the molecular response to fluralaner.


Assuntos
Isoxazóis/farmacologia , Spodoptera/efeitos dos fármacos , Spodoptera/genética , Transcriptoma/genética , Animais , Sistema Enzimático do Citocromo P-450/genética , Perfilação da Expressão Gênica/métodos , Inativação Metabólica/efeitos dos fármacos , Inativação Metabólica/genética , Proteínas de Insetos/genética , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Larva/genética , Pupa/efeitos dos fármacos , RNA-Seq/métodos , Regulação para Cima/genética , Sequenciamento Completo do Exoma/métodos
11.
Chemosphere ; 248: 125904, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32014633

RESUMO

Cadmium (Cd) pollution is widespread in paddy filed soil in China. In this study, the toxicity of Cd with regard to the female reproductive system of paddy spider Pardosa pseudoannulata was investigated by means of multi-omics analyses (transcriptome, proteome, and miRNAs). Decreased activities of detoxifying enzymes including peroxidase (POD), Glutathione S-transferases (GST), and superoxide dismutase were detected in the ovary of P. pseudoannulata. Of these, GST and POD were consistently down-regulated at the transcriptional and translational levels. Vitellogenin content and fecundity of the spider were also reduced by Cd burden. Five vitellogenin encodes genes were down-regulated while only vitellogenin-6 protein was up-regulated. But protein lipovitellin-1, the main composition of vitellin, was down-regulated. In addition, the correlation between the mitogen-activated protein kinase (MAPK) signaling pathway and Cd stress was identified. A down-regulated gene that encoding connector of kinase to AP-1 in the MAPK signaling pathway was regulated by the up-regulated miRNA (miRNA id: miRNA dan-miR- 318>der-miR-318>dgr-miR-318>dme-miR-318-3p > dmo-miR-318>dpe-miR-318>dps-miR-318>dse-miR-318>dsi-miR-318>dvi-miR-318>dwi-miR-318>dya-miR-318). In conclusion, Cd stress possesses distinct female reproductive toxicity on P. pseudoannulata through impairing antioxidant system and synthesis of vitellin.


Assuntos
Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Ovário/efeitos dos fármacos , Aranhas/efeitos dos fármacos , Animais , China , Feminino , Inativação Metabólica/genética , MicroRNAs , Aranhas/fisiologia , Superóxido Dismutase/genética , Transcriptoma
12.
J Biol Chem ; 295(7): 1829-1842, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31896576

RESUMO

The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largely-redundant roles. However, whereas examination of metabolomics data from Oat-knockout mice (Oat1 and Oat3KO) revealed considerable overlap, over a hundred metabolites were increased in the plasma of one or the other of these knockout mice. Many of these relatively unique metabolites are components of distinct biochemical and signaling pathways, including those involving amino acids, lipids, bile acids, and uremic toxins. Cheminformatics, together with a "logical" statistical and machine learning-based approach, identified a number of molecular features distinguishing these unique endogenous substrates. Compared with OAT1, OAT3 tends to interact with more complex substrates possessing more rings and chiral centers. An independent "brute force" approach, analyzing all possible combinations of molecular features, supported the logical approach. Together, the results suggest the potential molecular basis by which OAT1 and OAT3 modulate distinct metabolic and signaling pathways in vivo As suggested by the Remote Sensing and Signaling Theory, the analysis provides a potential mechanism by which "multispecific" kidney proximal tubule transporters exert distinct physiological effects. Furthermore, a strong metabolite-based machine-learning classifier was able to successfully predict unique OAT1 versus OAT3 drugs; this suggests the feasibility of drug design based on knockout metabolomics of drug transporters. The approach can be applied to other SLC and ATP-binding cassette drug transporters to define their nonredundant physiological roles and for analyzing the potential impact of drug-metabolite interactions.


Assuntos
Metabolômica , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Toxinas Biológicas/metabolismo , Trifosfato de Adenosina/genética , Animais , Ácidos e Sais Biliares/metabolismo , Transporte Biológico/genética , Humanos , Inativação Metabólica/genética , Túbulos Renais Proximais/metabolismo , Aprendizado de Máquina , Camundongos , Camundongos Knockout , Proteína 1 Transportadora de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Transdução de Sinais
13.
J Clin Oncol ; 38(6): 548-557, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31800347

RESUMO

PURPOSE: To examine the association between CYP2D6 genotype, discontinuation of tamoxifen therapy, and prognosis for breast cancer. PATIENTS AND METHODS: We conducted a prospective-retrospective study linking data from a clinical breast cancer register, the Swedish Prescribed Drug Register, and self-reported questionnaires. We genotyped CYP2D6 in 1,309 patients with breast cancer who were treated with tamoxifen and were diagnosed from 2005 to 2012; they were categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. We investigated whether metabolizer status was associated with tamoxifen discontinuation and prognosis for breast cancer using Cox regression analysis. RESULTS: The 6-month discontinuation rates of tamoxifen among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 7.1%, 7.6%, 6.7%, and 18.8%, respectively. A U-shaped association was found between CYP2D6 metabolizer status and breast cancer-specific mortality, with adjusted hazard ratios of 2.59 (95% CI, 1.01 to 6.67) for poor, 1.48 (95% CI, 0.72 to 3.05) for intermediate, 1 (reference) for normal, and 4.52 (95% CI, 1.42 to 14.37) for ultrarapid CYP2D6 metabolizers. CONCLUSION: Both poor and ultrarapid CYP2D6 metabolizers of tamoxifen have a worse prognosis for breast cancer compared with normal metabolizers after receiving a standard dose of tamoxifen. This U-shaped association might call for individualized tamoxifen dosage.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/metabolismo , Feminino , Genótipo , Humanos , Inativação Metabólica/genética , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Tamoxifeno/metabolismo
14.
Arch Insect Biochem Physiol ; 103(4): e21653, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31859418

RESUMO

Terpinen-4-ol has high fumigating activity to stored-grain pests including Tribolium confusum. To understand the detoxification of terpinen-4-ol in insects, proteomic analysis was performed to identify related proteins and pathways in response to terpinen-4-ol fumigation in T. confusum. By using isobaric tags for relative and absolute quantitation (iTRAQ)-based strategy, 4,618 proteins were obtained from T. confusum adults in the present study. Comparative proteomic analysis showed that 148 proteins were upregulated and 137 proteins were downregulated in beetles under the LC50 of terpinen-4-ol treatment for 24 hr. According to functional classifications, differentially expressed proteins (DEPs) were enriched in xenobiotic metabolism pathways. In the detoxification pathway, the levels of 25 cytochrome P450s, 5 glutathione S-transferases, and 2 uridine diphosphate (UDP)-glucuronosyltransferases were changed, most of which were upregulated in T. confusum exposed to terpinen-4-ol. The results indicated that terpinen-4-ol was potentially metabolized and detoxified by enzymes like P450s in T. confusum.


Assuntos
Fumigação , Inativação Metabólica/genética , Controle de Insetos , Proteínas de Insetos/genética , Terpenos/farmacologia , Tribolium/efeitos dos fármacos , Animais , Regulação para Baixo/genética , Proteínas de Insetos/metabolismo , Tribolium/metabolismo , Regulação para Cima/genética
15.
J Clin Oncol ; 38(6): 558-566, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31821071

RESUMO

PURPOSE: In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether CYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome. METHODS: Patients who needed first-line tamoxifen therapy were enrolled. Based on individual CYP2D6 genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes. RESULTS: Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% v 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM v 51.1 nM; P < .0001) and were also higher compared with wt/wt patients (72.0 nM; P = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months (P = .43). CONCLUSION: In patients with CYP2D6-variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Medicina de Precisão , Tamoxifeno/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/metabolismo , Antineoplásicos Hormonais/farmacocinética , Feminino , Genótipo , Humanos , Inativação Metabólica/genética , Japão , Pessoa de Meia-Idade , Medicina de Precisão/métodos , Intervalo Livre de Progressão , Tamoxifeno/metabolismo , Tamoxifeno/farmacocinética
16.
Xenobiotica ; 50(1): 92-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31601149

RESUMO

The carboxylesterase drug hydrolysis pathway has been used extensively to improve the oral availability of drugs under the assumption that the high capacity and low substrate specificity of hydrolytic enzymes would ensure rapid, complete, and consistent conversion of prodrugs to their active metabolite. However, a growing body of literature indicates that drug hydrolysis is usually catalyzed by one primary enzyme, either carboxylesterase-1 or carboxlylesterase-2, and that there is wide variability in enzyme activity affecting the metabolism of prodrugs to their active metabolites.This review identifies carboxylesterase substrates and describes our current understanding of the influence of genetic polymorphisms on substrate disposition and clinical effects. Several polymorphisms are described in the literature and included in the personalized medicine database PharmGKB, but there are no carboxylesterase genotypes referenced in Food and Drug Administration approved drug labeling. The limited validation of metabolic pathways for drugs undergoing hydrolysis, and the small number of studies evaluating genotype-drug interactions confirm that this is an emerging field of drug metabolism research.The dependence of prodrugs, many with low therapeutic indexes, on carboxylesterase-mediated hydrolysis indicate that genetic variation plays an important role in prodrug activation, and that carboxylesterase genotyping will become an important component of personalized medicine.


Assuntos
Hidrolases de Éster Carboxílico/genética , Medicina de Precisão , Hidrolases de Éster Carboxílico/metabolismo , Interações Medicamentosas , Genótipo , Humanos , Hidrólise , Inativação Metabólica/genética , Taxa de Depuração Metabólica , Polimorfismo Genético , Pró-Fármacos , Especificidade por Substrato
17.
Chemosphere ; 242: 125203, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31678848

RESUMO

Insect glutathione S-transferases (GSTs) are important in insecticide detoxification and Insect-specific GSTs, Epsilon and Delta, have largely expanded in insects. In this study, we functionally expressed and characterized an epsilon class GST gene (BdGSTe8), predominant in the adult Malpighian tubules of Bactrocera dorsalis. This gene may be associated with malathion resistance based on transcriptional studies of resistant and susceptible strains. RNA interference-mediated knockdown of this gene significantly recovered malathion susceptibility in the adults of a malathion-resistant strain, and overexpression of BdGSTe8 enhanced resistance in transgenic Drosophila. Analysis of BdGSTe8 polymorphism showed that several point mutations may be associated with metabolic resistance to malathion. A cytotoxicity assay in Escherichia coli indicated that both of the recombinant BdGSTe8 proteins may play a functional role in protecting cells from toxicity. The allele of BdGSTe8-B conferred higher levels of malathion detoxification capability. Liquid chromatography and ultra-performance liquid chromatography-tandem mass spectrometry analysis showed that the BdGSTe8-A allele did not metabolize malathion directly. However, the BdGSTe8-B allele was involved in the direct metabolism of malathion, which was caused by a mutation in V128A. Further analysis of the sequence suggests that BdGSTe8 evolved rapidly. It maybe play the role of a backup gene and could become a new gene in the future in order to retain the ability of detoxification of malathion, which was driven by positive selection. These results suggest that divergent molecular evolution in BdGSTe8 has played a role in metabolic resistance to malathion in B. dorsalis.


Assuntos
Evolução Molecular , Glutationa Transferase/metabolismo , Resistência a Inseticidas/genética , Malation/farmacologia , Tephritidae/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Drosophila/efeitos dos fármacos , Drosophila/genética , Drosophila/fisiologia , Glutationa Transferase/genética , Inativação Metabólica/genética , Inseticidas/farmacologia , Malation/metabolismo , Tephritidae/genética , Tephritidae/fisiologia
18.
Bull Entomol Res ; 110(1): 57-67, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31217039

RESUMO

Glyphodes pyloalis Walker (Lepidoptera: Pyralididae) is a common pest in sericulture and has developed resistance to different insecticides. However, the mechanisms involved in insecticide resistance of G. pyloalis are poorly understood. Here, we present the first whole-transcriptome analysis of differential expression genes in insecticide-resistant and susceptible G. pyloalis. Clustering and enrichment analysis of DEGs revealed several biological pathways and enriched Gene Ontology terms were related to detoxification or insecticide resistance. Genes involved in insecticide metabolic processes, including cytochrome P450, glutathione S-transferases and carboxylesterase, were identified in the larval midgut of G. pyloalis. Among them, CYP324A19, CYP304F17, CYP6AW1, CYP6AB10, GSTs5, and AChE-like were significantly increased after propoxur treatment, while CYP324A19, CCE001c, and AChE-like were significantly induced by phoxim, suggesting that these genes were involved in insecticide metabolism. Furthermore, the sequence variation analysis identified 21 single nucleotide polymorphisms within CYP9A20, CYP6AB47, and CYP6AW1. Our findings reveal many candidate genes related to insecticide resistance of G. pyloalis. These results provide novel insights into insecticide resistance and facilitate the development of insecticides with greater specificity to G. pyloalis.


Assuntos
Inativação Metabólica/genética , Resistência a Inseticidas/genética , Mariposas/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/genética , Feminino , Perfilação da Expressão Gênica , Genes de Insetos , Masculino , Mariposas/genética , Polimorfismo de Nucleotídeo Único , Transcriptoma
19.
Xenobiotica ; 50(1): 19-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31317802

RESUMO

The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease.The majority of FMO-mediated metabolism in adult human liver is catalyzed by FMO3. Some drugs are metabolized in human liver predominantly by FMO3, but most drug substrates of FMO3 are metabolized also by other enzymes, particularly cytochromes P-450, and the FMO3-catalyzed reaction is not the major route of metabolism.Rare variants that severely affect production or activity of FMO3 cause the disorder trimethylaminuria and impair metabolism of drug substrates of FMO3. More common variants, particularly p.[(Glu158Lys);(Glu308Gly)], can moderately affect activity of FMO3 in vitro and reduce metabolism of drug substrates in vivo, in some cases increasing drug efficacy or toxicity.Common variants of FMO3 have been associated with a number of disorders, but additional studies are needed to confirm or refute such associations.Elevated plasma concentrations of trimethylamine N-oxide, a product of an FMO3-catalyzed reaction, have been implicated in certain diseases, particularly cardiovascular disease. However, the evidence is often contradictory and additional work is required to establish whether trimethylamine N-oxide is a cause, effect or biomarker of the disease.Genetic variants of other FMOs are also briefly discussed.


Assuntos
Inativação Metabólica/genética , Oxigenases/genética , Adulto , Humanos , Erros Inatos do Metabolismo , Metilaminas/urina , Oxigenases/metabolismo , Polimorfismo Genético
20.
Tumori ; 106(2): 87-94, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30514181

RESUMO

Colorectal cancer, one of the most frequent types of cancer worldwide, has a high mortality rate. Irinotecan (CPT-11) has been approved for the treatment of advanced or metastatic disease either as a single agent or, more commonly, as part of combined chemotherapeutic regimens. Treatment with irinotecan is often accompanied by severe toxicity (e.g. neutropenia and diarrhea) that can result in treatment interruption or cessation, thus jeopardizing the patient's prognosis and quality of life. Irinotecan is bioactivated into its metabolite SN-38, which is subsequently detoxified by uridine diphosphate-glucuronosyl transferases (mainly UGT1A1). Further, ABC transporters (i.e. ABCB1, ABCC1-ABCC6, and ABCG2) are responsible for drug efflux into bile and urine whereas OATP transporters (SLCO1B1) enable its influx from blood into hepatocytes. Genetic polymorphisms in these enzymes/pumps may result in increased systemic SN-38 level, directly correlating with toxicity. Contemporary research is focused on the clinical implementation of genetic screenings for validated gene variations prior to treatment onset, allowing tailored individual doses or treatment regimens.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Glucuronosiltransferase/genética , Irinotecano/uso terapêutico , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportadores de Cassetes de Ligação de ATP/genética , Neoplasias Colorretais/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Genótipo , Humanos , Inativação Metabólica/genética , Irinotecano/efeitos adversos , Farmacogenética/tendências , Polimorfismo de Nucleotídeo Único/genética , Medicina de Precisão/tendências
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