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1.
Medicine (Baltimore) ; 99(11): e19444, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176075

RESUMO

BACKGROUND: In recent years, there has been an interest in whether environmental endocrine disruptors (EEDs) may contribute to the endocrine disorders in patients with polycystic ovary syndrome (PCOS). The clearance of EEDs from the human body is regulated by the glucuronidation of UDP-glucuronosyltransferases (UGT). This study aimed to analyze the relationship of UGT1A1, UGT2B7, and UGT2B15 polymorphisms with the metabolism of EEDs in patients with PCOS. METHODS: A total of 357 Chinese women (119 PCOS cases and 238 controls) were genotyped for polymorphisms of UGT1A1, UGT2B7, and UGT2B15. The plasma concentrations of EEDs were measured by the gas chromatography-mass spectrometry method. The association between UGT polymorphisms and the serum level of EEDs in patients with PCOS was analyzed. RESULTS: The UGT2B7 single nucleotide polymorphism was associated with an increased risk of PCOS. The homozygous polymorphism (TT) of UGT2B7 showed higher bisphenol A and PAEs concentrations in serum. However, a single nucleotide polymorphism on UGT2B15 expression was associated with a decreased risk of PCOS. Subjects homozygous for the T allele of UGT2B15 had a significant effect on phthalates in the blood. In addition, our results also showed that the homozygous polymorphism (TT) of UGT2B7 and UGT2B15 was associated with the capacity of the excretion of androgen in patients with PCOS. CONCLUSIONS: Our study reported the novel associations between the UGT polymorphisms and EEDs concentrations in patients with PCOS, supporting the relevance of genetic differences in EEDs metabolism, which might be considered as an etiology of PCOS.


Assuntos
Disruptores Endócrinos/metabolismo , Glucuronosiltransferase/genética , Síndrome do Ovário Policístico/etiologia , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Criança , Disruptores Endócrinos/toxicidade , Exposição Ambiental , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Genótipo , Humanos , Síndrome do Ovário Policístico/enzimologia , Polimorfismo de Nucleotídeo Único , Risco
2.
Gene ; 736: 144409, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007587

RESUMO

OBJECTIVE: To identify the association between UGT1A1 Gly71Arg and TATA promoter polymorphisms and neonatal hyperbilirubinemia. METHODS: The studies related to the correlation between UGT1A1 Gly71Arg and TATA promoter polymorphisms and neonatal hyperbilirubinemia were searched systematically in various databases. According to the presence or absence of significant heterogeneity, a random-effect or fixed-effect model was chosen to estimate the overall odds rations (ORs) and 95% confidence intervals (CIs). RESULTS: Totally 21 studies on Gly71Arg polymorphism including 4738 neonates and 13 studies on TATA promoter polymorphism involving 2841 neonates were identified. Significant associations were presented between Gly71Arg polymorphism and neonatal hyperbilirubinemia in Asia [A vs. G, OR(95%CI): 2.327(1.904-2.845), P < 0.001; AA + GA vs. GG, OR(95%CI): 2.253(1.954-2.598), P < 0.001; AA vs. GG + GA, OR(95%CI): 5.166(3.520-7.564), P < 0.001; AA vs. GG, OR(95%CI): 6.458(4.376-9.531), P < 0.001; GA vs. GG, OR(95%CI): 1.920(1.654-2.228), P < 0.001] and Africa [A vs. G, OR(95% CI): 9.750(1.214-78.301), P = 0.032; AA + GA vs. GG, OR(95% CI): 11.000(1.290-93.832), P = 0.028; GA vs. GG, OR(95% CI): 10.000(1.163-85.998), P = 0.036]. TATA promoter polymorphism was associated with an increased risk of neonatal hyperbilirubinemia in Asia [TA7/7 vs. TA6/6 + TA6/7, OR(95%CI): 1.670(1.034-2.696), P = 0.036] and Europe [TA7/7 vs. TA6/6 + TA6/7, OR(95%CI): 2.627(1.722-4.008), P < 0.001]. CONCLUSION: The risk of neonatal hyperbilirubinemia may be increased by the variation of UGT1A1 Gly71Arg in Asia and Africa, as well as the variation of UGT1A1 TATA promoter in Asia and Europe.


Assuntos
Predisposição Genética para Doença/genética , Glucuronosiltransferase/genética , Hiperbilirrubinemia Neonatal/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , África , Animais , Ásia , Estudos de Casos e Controles , Europa (Continente) , Humanos
3.
J Agric Food Chem ; 68(7): 2063-2070, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32009392

RESUMO

Luteolin is a typical flavonoid and broadly distributed in the plants. Oral bioavailability of luteolin is low owing to extensive metabolism. Regioselective glucuronidation by UDP-glucuronosyltransferases (UGTs) and liver uptake by organic anion transporting polypeptides (OATPs) of luteolin and consequent glucuronidation metabolites were studied. Luteolin-3'-O-glucuronide (L-3'-G) and luteolin-7-O-glucuronide (L-7-G) were the major metabolites in human liver microsomes. Further study demonstrated that UGT1A9 played a predominant role in the glucuronidation of luteolin. Transporter study showed that OATP1B1- and 1B3-transfected cells selectively uptake L-3'-G into cells but not luteolin or L-7-G. After intravenous administration of luteolin to mice, the area under the curve of L-3'-G in the plasma was the highest among luteolin, L-3'-G, and L-7-G. In the liver, the concentration of L-3'-G was significantly greater than L-7-G. In conclusion, OATP1B1 and OATP1B3 play an important role in the liver disposition of luteolin and its glucuronidation metabolites.


Assuntos
Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/metabolismo , Luteolina/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Transporte Biológico , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Luteolina/química , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética
4.
Xenobiotica ; 50(1): 64-76, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31092094

RESUMO

The role that the phase-II reaction, glucuronidation, plays in the biotransformation of endo and xenobiotics is discussed with particular emphasis given to the UGT1A1 isoenzyme. This individual isoenzyme is responsible for both the mono and di-glucuronidation of bilirubin together with the glucuronidation of a number of xenobiotics of clinical interest (irinotecan, belinostat, atazanavir, pegvisomant).The review then discusses the roles that the various allelic variants of the UGT1A1 gene play in bilirubin metabolism and in particular how these allelic variants are involved in the clinical manifestation of the diseases of GS, CN1 and CN2.The review concludes with the roles that the UGT1A1*28 and UGT1A1*6 alleles play in adverse drug reactions (decreased glucuronidation of irinotecan, belinostat, atazanavir, pegvisomant) leading to increased exposure, reduced clearance and neutropenia (irinotecan, belinostat), increased risk for jaundice and hyperbilirubinaemia (atazanavir) and liver toxicity (pegvisomant) before discussing the future role of UGT1A1 in personalised medicine.


Assuntos
Glucuronosiltransferase/genética , Alelos , Bilirrubina , Genótipo , Glucuronosiltransferase/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Hiperbilirrubinemia/metabolismo , Irinotecano/metabolismo , Sulfonamidas/metabolismo
5.
Insect Sci ; 27(2): 276-291, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30136378

RESUMO

Uridine diphosphate (UDP)-glycosyltransferases (UGTs) are widely distributed within living organisms and share roles in biotransformation of various lipophilic endo- and xenobiotics with activated UDP sugars. In this study, it was found that the activity of UGTs in abamectin-resistant (AbR) strain was significantly higher (2.35-fold) than that in susceptible strain (SS) of Tetranychus cinnabarinus. Further analysis showed that 5-nitrouracil, the inhibitor of UGTs, could enhance the lethal effect of abamectin on mites. From the previous microarray results, we found an UGT gene (UGT201D3) overexpressed in AbR strain. Quantitative PCR analysis showed that UGT201D3 was highly expressed and more inducible with abamectin exposure in the AbR strain. After silencing the transcription of UGT201D3, the activity of UGTs was decreased and the susceptibility to abamectin was increased in AbR strain whereas it was not in SS. Furthermore, UGT201D3 gene was then successfully expressed in Escherichia coli. The recombinant UGT201D3 exhibited α-naphthol activity (2.81 ± 0.43 nmol/mg protein/min), and the enzyme activity could be inhibited by abamectin (inhibitory concentration at 50%: 57.50 ± 3.54 µmol/L). High-performance liquid chromatography analysis demonstrated that the recombinant UGT201D3 could effectively deplete abamectin (15.77% ± 3.72%) incubating with 150 µg protein for 6 h. These results provided direct evidence that UGT201D3 was involved in abamectin resistance in T. cinnabarinus.


Assuntos
Glucuronosiltransferase/metabolismo , Inseticidas , Ivermectina/análogos & derivados , Tetranychidae/metabolismo , Sequência de Aminoácidos , Animais , Escherichia coli , Feminino , Glucuronosiltransferase/genética , Resistência a Inseticidas , Interferência de RNA , Tetranychidae/genética , Uracila/análogos & derivados
6.
Niger J Clin Pract ; 22(10): 1319-1323, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31607718

RESUMO

Background: Morphine is a common analgesic often used to manage chronic pain, especially for patients with pain due to malignancies. Since UGT2B7 plays an important role in the metabolism of morphine, UGT2B7 gene mutation may influence the efficacy of morphine in patients with cancer being treated by this medication. Aims: The aim of this study is to investigate the relationship between the polymorphisms of UGT2B7 and the efficacy of morphine treatment on cancer pain among the Chinese Han population. Materials and Methods: A total of 120 patients with cancer pain were enrolled in this study. Morphine was administrated through patient-controlled analgesia infusion pump, and the visual analog score (VAS) was used for pain assessment at 0.5, 4, 6, 12, 24, 48, and 72-h post morphine treatment, respectively. The plasma concentration of morphine and genetic polymorphism of UGT2B7 C802T and G221T was analyzed, respectively. Results: The frequencies of UGT2B7 C802T were CC: 13.33%, CT: 45% and TT: 41.67%, and the frequencies of UGT2B7 G221T were GG: 76.67%, GT: 22.5% and TT: 0.83%. Moreover, the VAS score of patients with either C802T CT or TT was significantly higher than that in patients with C802T CC. However, no difference of VAS scores was observed between patients carrying G221T GG and patients carrying G221T GT. The plasma concentration of morphine for patients with the C802T CC was significantly lower than that in patients carrying C802T CT or TT, while there was no significant difference in the level of morphine between patients with G221T GG and G221T GT. Conclusion: The polymorphism of UGT2B7 C802T, but not UGT2B7 G221T, has been associated with the efficacy of morphine treatment on cancer pain among Chinese Han population.


Assuntos
Analgésicos Opioides/sangue , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Dor do Câncer/tratamento farmacológico , Glucuronosiltransferase/genética , Morfina/sangue , Neoplasias/sangue , Polimorfismo Genético/genética , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Dor do Câncer/genética , Feminino , Genótipo , Humanos , Bombas de Infusão , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Morfina/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medição da Dor , Escala Visual Analógica
7.
BMC Med Genet ; 20(1): 160, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619193

RESUMO

BACKGROUND: (TA) n repeat sequence (rs8175347) of UGT1A1 gene promoter polymorphism is associated with serum bilirubin levels and gallstones among different sickle cell anaemia (SCA) populations. There are no data on UGT1A1 polymorphisms and their impact on Nigerian SCA patients. In this study, we determined the distribution of the UGT1A1 (TA) n genotypes among a group of young Nigerian SCA patients and healthy controls. In addition, the influence of UGT1A1 (TA) n genotypes on the laboratory and clinical events among the patients was determined. METHODS: The distribution of the UGT1A1 (TA) n genotypes among 101 young Nigerian SCA patients and 64 normal appropriate controls were determined and studied. The UGT1A1 (TA) n genotypes were further classified into subgroups and used to differentiate the clinical events and laboratory parameters of the patients. RESULTS: Four (TA) n alleles:(TA)5, 6, 7, and 8 were found. These were associated with 10 genotypes: TA5/5, 5/6, 5/7, 5/8, 6/6, 6/7, 6/8, 7/7, 7/8, 8/8. The normal (wild-type)-(TA) 6/6), low- (TA) 7/7, 7/8, 8/8), intermediate- (TA) 5/7, 5/8, 6/7, 6/8), and high-activity (TA) 5/5, 5/6,) genotypes were found in 24.8, 24.8, 41.5, and 8.9% patients and 20.3, 15.6, 61, and 3.1% controls respectively. The general genotype distribution of the patients and control group were not significantly different. There were significant differences in serum bilirubin and lactate dehydrogenase (LDH) of the patients when differentiated by the UGT1A1 (TA) n genotypes (p<0.05). Asymptomatic gallstones were found in 5.9% of patients and were significantly of the low-activity genotypes sub-group 5 (20%) vs 1(1.3%) p = 0.0033. Although, bilirubin and fetal hemoglobin (HbF) of patients with gallstones were significantly different from those without gallstone, only the serum bilirubin was associated with UGT1A1 (TA) n genotypes on multivariate analysis (p < 0.0001). CONCLUSION: This study highlights the contribution of UGT1A1 polymorphisms, a non-globin genetic factor, to the laboratory and clinical manifestations of young Nigerian SCA patients for the first time. It also shows that children with co-inheritance of low UGT1A1 (TA) n affinity genotypes may be at risk of gallstone, hence the need to follow them up.


Assuntos
Anemia Falciforme/genética , Glucuronosiltransferase/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adolescente , Anemia Falciforme/complicações , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Cálculos Biliares/complicações , Cálculos Biliares/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Nigéria , Adulto Jovem
8.
PLoS Negl Trop Dis ; 13(9): e0007687, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513587

RESUMO

Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori, affects millions of people worldwide. Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by limitations of current anti-filarial drugs and the lack of a vaccine. The goal of this study was to evaluate B. malayi intestinal UDP-glucuronosyltransferase (Bm-UGT) as a potential therapeutic target. To evaluate whether Bm-UGT is essential for adult filarial worms, we inhibited its expression using siRNA. This resulted in a 75% knockdown of Bm-ugt mRNA for 6 days and almost complete suppression of detectable Bm-UGT by immunoblot. Reduction in Bm-UGT expression resulted in decreased worm motility for 6 days, 70% reduction in microfilaria release from adult worms, and significant reduction in adult worm metabolism as detected by MTT assays. Because prior allergic-sensitization to a filarial antigen would be a contraindication for its use as a vaccine candidate, we tested plasma from infected and endemic normal populations for Bm-UGT-specific IgE using a luciferase immunoprecipitation assay. All samples (n = 35) tested negative. We then tested two commercially available medicines known to be broad inhibitors of UGTs, sulfinpyrazone and probenecid, for in vitro activity against B. malayi. There were marked macrofilaricidal effects at concentrations achievable in humans and very little effect on microfilariae. In addition, we observed that probenecid and sulfinpyrazone exhibit a synergistic macrofilaricidal effect when used in combination with albendazole. The results of this study demonstrate that Bm-UGT is an essential protein for adult worm survival. Lack of prior IgE sensitization in infected and endemic populations suggest it may be a feasible vaccine candidate. The finding that sulfinpyrazone and probenecid have in vitro effects against adult B. malayi worms suggests that these medications have promise as potential macrofilaricides in humans.


Assuntos
Brugia Malayi/efeitos dos fármacos , Brugia Malayi/enzimologia , Glucuronosiltransferase/metabolismo , Albendazol/farmacologia , Animais , Antígenos de Helmintos/sangue , Brugia Malayi/imunologia , Brugia Malayi/metabolismo , Quimioterapia Combinada , Filariose Linfática/tratamento farmacológico , Filariose Linfática/prevenção & controle , Feminino , Filaricidas/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/genética , Humanos , Imunoglobulina E/sangue , Intestinos/enzimologia , Microfilárias/efeitos dos fármacos , Movimento , Probenecid/farmacologia , RNA Interferente Pequeno , Sulfimpirazona/farmacologia
9.
Medicina (Kaunas) ; 55(9)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547335

RESUMO

Pain can have a significantly negative impact on the quality of life of patients. Therefore, patients may resort to analgesics to relieve the pain. The struggle to manage pain in cancer patients effectively and safely has long been an issue in medicine. Analgesics are the mainstay treatment for pain management as they act through various methods on the peripheral and central pain pathways. However, the variability in the patient genotypes may influence a drug response and adverse drug effects that follow through. This review summarizes the observed effects of analgesics on UDP-glucuronosyl (UGT) 2B7 isoenzyme, cytochrome P450 (CYP) 2D6, µ-opioid receptor µ 1 (OPRM1), efflux transporter P-glycoprotein (P-gp) and ATP-binding cassette B1 ABCB1/multiple drug resistance 1 (MDR1) polymorphisms on the mechanism of action of these drugs in managing pain in cancer. Furthermore, this review article also discusses the responses and adverse effects caused by analgesic drugs in cancer pain management, due to the inter-individual variability in their genomes.


Assuntos
Analgésicos/uso terapêutico , Dor do Câncer/tratamento farmacológico , Redes Reguladoras de Genes , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Dor do Câncer/genética , Citocromo P-450 CYP2D6/genética , Glucuronosiltransferase/genética , Humanos , Manejo da Dor/métodos , Variantes Farmacogenômicos , Qualidade de Vida , Receptores Opioides mu/genética
10.
Genes (Basel) ; 10(9)2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438591

RESUMO

The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.


Assuntos
Fenótipo de Síndrome de Antley-Bixler/genética , Aracnodactilia/genética , Doenças Ósseas/congênito , Craniossinostoses/genética , Nanismo/genética , Glucuronosiltransferase/genética , Síndrome de Marfan/genética , Mutação , Osteocondrodisplasias/genética , Fenótipo , Dermatopatias Genéticas/genética , Adolescente , Fenótipo de Síndrome de Antley-Bixler/patologia , Aracnodactilia/patologia , Doenças Ósseas/genética , Doenças Ósseas/patologia , Craniossinostoses/patologia , Nanismo/patologia , Feminino , Humanos , Síndrome de Marfan/patologia , Osteocondrodisplasias/patologia , Dermatopatias Genéticas/patologia
11.
Biomed Res Int ; 2019: 6272174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467903

RESUMO

Objective: The spectrum of UDP-glucuronyl transferase A1 (UGT1A1) variants in hereditary unconjugated hyperbilirubinemia varies markedly between different ethnic populations. This study evaluated the UGT1A1 genotypes in hyperbilirubinemia patients from southeastern China. Methods: We enrolled 60 patients from southeastern China (44 men and 16 women; age range: 3-76 years) with unconjugated hyperbilirubinemia and performed genetic analysis of the UGT1A1 gene by direct sequencing. Results: For patients with Gilbert syndrome, 85% (47/55) harbored pathogenic variants of UGT1A1⁎60. Both UGT1A1⁎28 and UGT1A1⁎81 were detected in the promoter region of UGT1A1. Additionally, 83% (20/24) of patients with Gilbert syndrome heterozygous for UGT1A1⁎60 had an association with heterozygous variation of UGT1A1⁎28 or UGT1A1⁎81, while 91% (21/23) of Gilbert syndrome patients homozygous for UGT1A1⁎60 had biallelic variations of UGT1A1⁎28 and UGT1A1⁎81. We detected 213 UGT1A1 allelic variants, including six novel variations, with the most frequent allele being the UGT1A1⁎60, followed by UGT1A1⁎28 and UGT1A1⁎6. All of the patients showed multiple sites of variants in UGT1A1; however, variation number was not associated with bilirubin levels (P>0.05). Conclusions: The spectrum of UGT1A1 variants in southeastern Chinese patients was distinct from other ethnic populations. Our findings broaden the knowledge concerning traits associated with UGT1A1 variants and help profile genotype-phenotype correlations in hyperbilirubinemia patients.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Glucuronosiltransferase/genética , Hiperbilirrubinemia/genética , Adolescente , Adulto , Idoso , Alelos , Bilirrubina/genética , Bilirrubina/metabolismo , Criança , Pré-Escolar , China , Feminino , Frequência do Gene , Genética Populacional , Genótipo , Humanos , Hiperbilirrubinemia/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
12.
Yi Chuan ; 41(6): 509-523, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31257199

RESUMO

UDP-glucuronosyltransferases (UGTs) are an important family of phase 2 drug-metabolizing enzymes that catalyze the glucuronidation of numerous endogenous or exogenous small compounds. The aberrant expression of UGT isoforms causes many diseases, such as hyperbilirubinemia and affect drug efficacy or toxicity. Understanding mechanisms of UGT gene regulation will provide scientific foundations for disease prevention and personalized or precision medicine. Vertebrate UGT family genes can be divided into UGT1 and UGT2 subfamilies. Similar to the protocadherin, immunoglobulin, and T-cell receptor gene clusters and different from the UGT2 gene cluster, the UGT1 gene cluster is organized into variable and constant regions. The UGT1 variable region contains a tandem array of variable exons, each of which can be alternatively spliced to a single set of 4 downstream constant exons, generating at least nine UGT1 mRNAs that could be translated into different UGT1 glucuronyltransferase isoforms. Our previous work reveals that the relative orientations and locations of CTCF binding sites play a key role in the three-dimensional organization of the mammalian genomes in cell nuclei. Thus in order to study the transcriptional mechanisms of UGT1 gene cluster, the distributions and orientations of CTCF binding sites (CBSs) are analyzed and compared between human and mouse UGT1 gene clusters. We find that the CBSs in the UGT1 gene cluster are not conserved between human and mouse species. We show that CTCF and cohesin regulate the transcription of the UGT1 gene cluster by knocking down the CTCF or the cohesin subunit SMC3 in the human A549 cell line. By using CRISPR DNA-fragment editing, we deleted and inverted hCBS1. By RNA-seq experiments, we find that hCBS1 deletion results in a significant decrease of levels of the UGT1A6, UGT1A7, and UGT1A9 gene expression and that hCBS1 inversion results in a significant decrease of levels of the UGT1A7 gene expression. Our data suggest that the CTCF binding site hCBS1 plays an important regulatory role in the regulation of UGT1 gene expression, providing an experimental basis for further mechanistic studies of the 3D genome regulation of the UGT1 gene cluster.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Regulação da Expressão Gênica , Glucuronosiltransferase/genética , Família Multigênica , Animais , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Éxons , Humanos , Camundongos , RNA Mensageiro
13.
Drug Metab Pharmacokinet ; 34(4): 280-286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31262603

RESUMO

UDP-Glucuronosyltransferase (UGT) 2A3 belongs to a UGT superfamily of phase II drug-metabolizing enzymes that catalyzes the glucuronidation of many endobiotics and xenobiotics. Previous studies have demonstrated that UGT2A3 is expressed in the human liver, small intestine, and kidney at the mRNA level; however, its protein expression has not been determined. Evaluation of the protein expression of UGT2A3 would be useful to determine its role at the tissue level. In this study, we prepared a specific antibody against human UGT2A3 and evaluated the relative expression of UGT2A3 in the human liver, small intestine, and kidney. Western blot analysis indicated that this antibody is specific to UGT2A3 because it did not cross-react with other human UGT isoforms or rodent UGTs. UGT2A3 expression in the human small intestine was higher than that in the liver and kidney. Via treatment with endoglycosidase, it was clearly demonstrated that UGT2A3 was N-glycosylated. UGT2A3 protein levels were significantly correlated with UGT2A3 mRNA levels in a panel of 28 human liver samples (r = 0.64, p < 0.001). In conclusion, we successfully prepared a specific antibody against UGT2A3. This antibody would be useful to evaluate the physiological, pharmacological, and toxicological roles of UGT2A3 in human tissues.


Assuntos
Anticorpos/imunologia , Glucuronosiltransferase/imunologia , Reações Antígeno-Anticorpo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Microssomos/imunologia , Microssomos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/imunologia , RNA Mensageiro/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Células Tumorais Cultivadas
14.
Int J Mol Sci ; 20(15)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349586

RESUMO

Uridine diphosphate (UDP)-glycosyltransferases (UGTs) are major phase II detoxification enzymes involved in glycosylation of lipophilic endobiotics and xenobiotics, including phytoalexins. Nicotine, one of the most abundant secondary plant metabolites in tobacco, is highly toxic to herbivorous insects. Plant-herbivore competition is the major impetus for the evolution of large superfamilies of UGTs and other detoxification enzymes. However, UGT functions in green peach aphid (Myzus persicae) adaptation are unknown. In this study, we show that UGT inhibitors (sulfinpyrazone and 5-nitrouracil) significantly increased nicotine toxicity in M. persicae nicotianae, suggesting that UGTs may be involved in nicotine tolerance. In total, 101 UGT transcripts identified in the M. persicae genome/transcriptome were renamed according to the UGT Nomenclature Committee guidelines and grouped into 11 families, UGT329, UGT330, UGT339, UGT341-UGT345, and UGT348-UGT350, with UGT344 containing the most (57). Ten UGTs (UGT330A3, UGT339A2, UGT341A6, UGT342B3, UGT343C3, UGT344D5, UGT344D8, UGT348A3, UGT349A3, and UGT350A3) were highly expressed in M. persicae nicotianae compared to M. persicae sensu stricto. Knockdown of four UGTs (UGT330A3, UGT344D5, UGT348A3, and UGT349A3) significantly increased M. persicae nicotianae sensitivity to nicotine, suggesting that UGT expression in this subspecies may be associated with nicotine tolerance and thus host adaptation. This study reveals possible UGTs relevant to nicotine adaptation in tobacco-consuming M. persicae nicotianae, and the findings will facilitate further validation of the roles of these UGTs in nicotine tolerance.


Assuntos
Adaptação Biológica , Afídeos/fisiologia , Glucuronosiltransferase/metabolismo , Nicotina/metabolismo , Sequência de Aminoácidos , Animais , Afídeos/classificação , Afídeos/efeitos dos fármacos , Sequência Conservada , Resistência a Medicamentos/genética , Expressão Gênica , Técnicas de Silenciamento de Genes , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/química , Glucuronosiltransferase/genética , Família Multigênica , Nicotina/farmacologia , Filogenia , Domínios Proteicos
15.
Toxicol In Vitro ; 60: 347-358, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31233785

RESUMO

Pregnane & Xenobiotic Receptor (PXR), one of the members of nuclear receptor superfamily, acts as a 'master-regulator' of drug metabolism and disposition machinery (DMD). Activation of PXR enables detoxification and elimination of toxic xenobiotics/endobiotics, and defends our body against chemical insults. On the contrary, PXR activation also imposes a serious concern for drug-drug interactions (DDIs). Such DDIs could either decrease the efficacy or lead to accumulation of co-administered drugs at toxic level. Therefore, it is desirable that during drug development process the small drug molecules are screened on PXR-platform prior to their clinical trial and prevent late stage failures. In view of this, we have selected a group of anti-diabetic drug molecules to examine if the success and potential failure of small molecule modulators can be pre-assessed and judiciously correlated on PXR platform. For this purpose, we have examined the PXR activation potential of the selected anti-diabetic drugs. Subsequent to screening of these anti-diabetic drugs, we elaborated the study further with rosiglitazone and pioglitazone (thiazolidinediones, TZDs) which are oral anti-diabetic formulations and have been in controversy owing to their association with cardiotoxicity and bladder cancer respectively. Our study revealed that some of the selected anti-diabetic drugs possess PXR activation potential, implying that these can up-regulate the expression of CYP3A4, UGT1A1, MDR1 and thereby can be predicted to inflict undesirable consequences.


Assuntos
Hipoglicemiantes/farmacologia , Receptor de Pregnano X/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Linhagem Celular , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interações de Medicamentos , Glucuronosiltransferase/genética , Humanos , Pioglitazona/farmacologia , Receptor de Pregnano X/genética , RNA Interferente Pequeno/genética , Rosiglitazona/farmacologia
16.
PLoS One ; 14(5): e0217695, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31150474

RESUMO

Demethoxycurcumin (DMC) is a safe and natural food-coloring additive, as well as an agent with several therapeutic properties. However, extensive glucuronidation in vivo has resulted in its poor bioavailability. In this study, we aimed to investigate the formation of DMC-O-glucuronides by uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and its transport by breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa cells stably transfected with UGT1A1 (named HeLa1A1 cells). The chemical inhibitors Ko143 (a selective BCRP inhibitor) and MK571 (a pan-MRP inhibitor) both induced an obvious decrease in the excretion rate of DMC-O-glucuronides and a significant increase in intracellular DMC-O-glucuronide concentrations. Furthermore, BCRP knock-down resulted in a marked reduction in the level of excreted DMC-O-glucuronides (maximal 55.6%), whereas MRP1 and MRP4 silencing significantly decreased the levels of excreted DMC-O-glucuronides (a maximum of 42.9% for MRP1 and a maximum of 29.9% for MRP3), respectively. In contrast, neither the levels of excreted DMC-O-glucuronides nor the accumulation of DMC-O-glucuronides were significantly altered in the MRP4 knock-down HeLa cells. The BCRP, MRP1 and MRP3 transporters were identified as the most important contributors to the excretion of DMC-O-glucuronides. These results may significantly contribute to improving our understanding of mechanisms underlying the cellular disposition of DMC via UGT-mediated metabolism.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Diarileptanoides/farmacologia , Glucuronosiltransferase/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Disponibilidade Biológica , Diarileptanoides/química , Dicetopiperazinas/farmacologia , Corantes de Alimentos/química , Corantes de Alimentos/farmacologia , Inativação Gênica , Glucuronídeos/biossíntese , Glucuronídeos/genética , Glucuronosiltransferase/química , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Propionatos/farmacologia , Transporte Proteico/genética , Quinolinas/farmacologia , Transfecção
17.
Gan To Kagaku Ryoho ; 46(4): 754-756, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164525

RESUMO

Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Glucuronosiltransferase/genética , Neoplasias Pancreáticas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Polimorfismo Genético
18.
Clin Biochem ; 71: 67-68, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247186

RESUMO

Two Chinese female infants from two unrelated families were diagnosed with Crigler-Najjar syndromes-I (CNS-I) and CNS-II respectively. The CNS-I patient had Serum Total Bilirubin Concentration (STBC) peaked at 26.1 mg/dL. She was not responsive to Phenobarbital and received liver transplantation at 2-year-old. The CNS-II patient's STBC fluctuated between 10.2 mg/dL and 17.4 mg/dL and had a milder phenotype. Sequencing of Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) revealed the CNS-I patient carried a heterozygous pathogenic variant in c.392 T > C (p.Leu131Pro) and the CNS-II patient carried a heterozygous pathogenic variant in c.1456 T > G (p.Tyr486Asp). Furthermore, a novel deletion spanning exons 2-4 of UGT1A1 were detected in both patients. We studied two family members' genotyping results of UGT1A1 to clarify the inheritance of this microdeletion. To our knowledge, this is probably the first time showing 2 CNS cases both carrying compound heterozygous variations of a known pathogenic variant and a novel microdeletion.


Assuntos
Síndrome de Crigler-Najjar/genética , Deleção de Genes , Glucuronosiltransferase/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Humanos , Lactente , Masculino , Linhagem
19.
BMC Med Genomics ; 12(1): 81, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159795

RESUMO

BACKGROUND: Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. METHODS: A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. RESULTS: Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. CONCLUSIONS: PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Medicina de Precisão/métodos , Adulto , Criança , Simulação por Computador , Citocromo P-450 CYP2D6/genética , Variações do Número de Cópias de DNA , Glucuronosiltransferase/genética , Humanos , Anotação de Sequência Molecular
20.
Gene ; 706: 115-123, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31082503

RESUMO

BACKGROUND: UGT2B7 was recently acknowledged as a new critical enzyme involved in biotransformation of a variety of carcinogens, whose function was reported to be significantly associated with its encoding gene (UGT2B7) polymorphisms. However, results regarding the associations between single nucleotide polymorphisms (SNPs) of UGT2B7 and cancer risk still remained controversial. Therefore, a meta-analysis was conducted to further elucidate the role of UGT2B7 SNPs on cancer susceptibilities. METHODS: PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP) and Wan Fang Database were searched for eligible studies until March 2019. All analysis was carried out using the Review Manager 5.3 software. Subgroup analyses were performed by cancer types, ethnicity or source of controls. RESULTS: 13 studies with a total of 7688 cancer cases and 11,281 controls were included in this meta-analysis. The results showed that UGT2B7 rs7439366 increased the colorectal cancer risk in dominant model (OR = 0.76, 95% CI = 0.61-0.95, P = 0.02). However, as for the rs7435335 and rs12233719, we did not find their associations with cancer risk in all genetic models. In addition, the rs7441774 was found to be associated with breast cancer risk and significantly reduced papillary thyroid cancer risk in rs3924194 was also observed. Nevertheless, these findings remained to be further proven in future studies since these 2 SNPs were only respectively involved in 1 study. CONCLUSION: This meta-analysis confirmed the association of UGT2B7 rs7439366 with colorectal cancer risk, which may be a potential promising biomarker for prediction of colorectal cancer risk.


Assuntos
Neoplasias Colorretais/genética , Glucuronosiltransferase/genética , Neoplasias/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Genótipo , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/fisiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
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