RESUMO
BACKGROUND: Benzo(a)pyrene (B[a]P) is the most widely concerned polycyclic aromatic hydrocarbons (PAHs), which metabolizes benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) in vivo to produce carcinogenic effect on the body. Currently, there is limited research on the role of the variation of metabolic enzymes in this process. METHODS: We carried out a study including 752 participants, measured the concentrations of 16 kinds PAHs in both particle and gaseous phases, urinary PAHs metabolites, leukocyte BPDE-DNA adduct and serum BPDE- Albumin (BPDE-Alb) adduct, and calculated daily intake dose (DID) to assess the cumulative exposure of PAHs. We conducted single nucleotide polymorphism sites (SNPs) of metabolic enzymes, explored the exposure-response relationship between the levels of exposure and BPDE adducts using multiple linear regression models. RESULT: Our results indicated that an interquartile range (IQR) increase in B[a]P, PAHs, BaPeq, 1-hydroxypyrene (1-OHP), 1-hydroxynaphthalene (1-OHNap) and 2-hydroxynaphthalene (2-OHNap) were associated with 26.53 %, 24.24 %, 28.15 %, 39.15 %, 12.85 % and 14.09 % increase in leukocyte BPDE-DNA adduct (all P < 0.05). However, there was no significant correlation between exposure with serum BPDE-Alb adduct (P > 0.05). Besides, we also found the polymorphism of CYP1A1(Gly45Asp), CYP2C9 (Ile359Leu), and UGT1A1(downstream) may affect BPDE adducts level. CONCLUSION: Our results indicated that leukocyte BPDE-DNA adduct could better reflect the exposure to PAHs. Furthermore, the polymorphism of CYP1A1, CYP2C9 and UGT1A1affected the content of BPDE adducts.
Assuntos
7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido , Adutos de DNA , Interação Gene-Ambiente , Hidrocarbonetos Policíclicos Aromáticos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , China , Citocromo P-450 CYP1A1/genética , Adutos de DNA/sangue , População do Leste Asiático/genética , Exposição Ambiental , Glucuronosiltransferase/genética , Leucócitos/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/sangue , Polimorfismo de Nucleotídeo Único , Citocromo P-450 CYP2C9/genéticaRESUMO
BACKGROUND: Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib. METHODS: We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia. RESULTS: Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed. CONCLUSION: We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase.
Assuntos
Anilidas , Carcinoma de Células Renais , Glucuronosiltransferase , Hiperbilirrubinemia , Indazóis , Neoplasias Renais , Piridinas , Pirimidinas , Sulfonamidas , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Glucuronosiltransferase/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/genética , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Anilidas/uso terapêutico , Anilidas/efeitos adversos , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Indazóis/uso terapêutico , Idoso , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Axitinibe/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/administração & dosagem , Bilirrubina/sangue , Genótipo , Adulto , Polimorfismo Genético , Idoso de 80 Anos ou maisRESUMO
PURPOSE: The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder. METHODS: A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21â days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping. RESULTS: The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [ UGT1A4 -142T>G and UGT2B7 -161C>T ( P â <â 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6â ±â 1.1 and 1.7â ±â 0.5â µg/ml per mg/kg) than those with the TT genotype (1.4â ±â 1.1â µg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6â ±â 1.1â µg/ml per mg/kg) than those with the CC genotype (1.3â ±â 1.3â µg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics ( P â <â 0.001). CONCLUSION: The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder.
Assuntos
Transtorno Bipolar , Glucuronosiltransferase , Lamotrigina , Triazinas , Humanos , Lamotrigina/sangue , Lamotrigina/farmacocinética , Lamotrigina/administração & dosagem , Lamotrigina/uso terapêutico , Glucuronosiltransferase/genética , Masculino , Feminino , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Transtorno Bipolar/sangue , Adulto , Triazinas/farmacocinética , Triazinas/sangue , Triazinas/administração & dosagem , Triazinas/uso terapêutico , Pessoa de Meia-Idade , Genótipo , Polimorfismo de Nucleotídeo Único/genética , Povo Asiático/genéticaRESUMO
PURPOSE: Predicting the quantitative fraction of glucuronidation (fgluc) by individual UDP-glucuronosyltransferase enzymes (UGTs) is challenging due to the lack of selective inhibitors and inconsistent activity of recombinant UGT systems (rUGTs). Our study compares the relative expression versus activity factors (REF versus RAF) to predict fgluc based on rUGT data to human liver and intestinal microsomes (HLM and HIM). METHODS: REF scalars were derived from a previous in-house proteomics study for eleven UGT enzymes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17), whereas RAF was calculated by measuring activities in rUGTs to microsomes of selective UGT probe substrates. Protein-normalized activity factor (pnAF) values were generated after correcting activity of individual UGTs to their corresponding protein abundance. The utility of REF and RAF in predicting fgluc was assessed for three UGT substrates-diclofenac, vorinostat, and raltegravir. RESULTS: The REF values ranged from 0.02 to 1.75, RAF based on activity obtained in rUGTs to HLM/HIM were from 0.1 to 274. pnAF values were ~ 5 to 80-fold, except for UGT2B4 and UGT2B15, where pnAF was ~ 180 and > 1000, respectively. The results revealed confounding effect of differential specific activities (per pmol) of rUGTs in fgluc prediction. CONCLUSION: The data suggest that the activity of UGT enzymes was significantly lower when compared to their activity in microsomes at the same absolute protein amount (pmol). Collectively, results of this study demonstrate poor and variable specific activity of different rUGTs (per pmol protein), as determined by pnAF values, which should be considered in fgluc scaling.
Assuntos
Glucuronídeos , Glucuronosiltransferase , Microssomos Hepáticos , Proteínas Recombinantes , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/genética , Humanos , Proteínas Recombinantes/metabolismo , Glucuronídeos/metabolismo , Microssomos Hepáticos/metabolismo , Microssomos/metabolismo , Diclofenaco/metabolismo , Taxa de Depuração Metabólica , Mucosa Intestinal/metabolismoRESUMO
End-ischemic normothermic mechanical perfusion (NMP) could provide a curative treatment to reduce cholestatic liver injury from donation after circulatory death (DCD) in donors. However, the underlying mechanism remains elusive. Our previous study demonstrated that air-ventilated NMP could improve functional recovery of DCD in a preclinical NMP rat model. Here, metabolomics analysis revealed that air-ventilated NMP alleviated DCD- and cold preservation-induced cholestatic liver injury, as shown by the elevated release of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and γ-glutamyl transferase (GGT) in the perfusate (p < .05) and the reduction in the levels of bile acid metabolites, including ω-muricholic acid, glycohyodeoxycholic acid, glycocholic acid, and glycochenodeoxycholate (GCDC) in the perfused livers (p < .05). In addition, the expression of the key bile acid metabolism enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is predominantly expressed in hepatocytes, was substantially elevated in the DCD rat liver, followed by air-ventilated NMP (p < .05), and in vitro, this increase was induced by decreased GCDC and hypoxia-reoxygenation in the hepatic cells HepG2 and L02 (p < .05). Knockdown of UGT1A1 in hepatic cells by siRNA aggravated hepatic injury caused by GCDC and hypoxia-reoxygenation, as indicated by the ALT and AST levels in the supernatant. Mechanistically, UGT1A1 is transcriptionally regulated by peroxisome proliferator-activator receptor-γ (PPAR-γ) under hypoxia-physoxia. Taken together, our data revealed that air-ventilated NMP could alleviate DCD- and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis. Based on the results from this study, air-ventilated NMP confers a promising approach for predicting and alleviating cholestatic liver injury through PPAR-γ/UGT1A1 axis.
Assuntos
PPAR gama , Animais , Ratos , PPAR gama/metabolismo , PPAR gama/genética , Masculino , Humanos , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/genética , Fígado/metabolismo , Fígado/patologia , Colestase/metabolismo , Perfusão , Ratos Sprague-Dawley , Preservação de Órgãos/métodos , Transplante de FígadoRESUMO
CYP2D6 variants contain various single nucleotide polymorphisms as well as differing levels of metabolic activity. Among these, one of the less active variants CYP2D6*10 (100C > T) is the most prevalent mutation in East Asians, including Japanese. This mutation leads to an amino acid substitution from proline to serine, which reduces the stability of CYP2D6 and consequently decreases its metabolic activity. In this study, we used a genome editing technology called the Precise Integration into Target Chromosome (PITCh) system to stably express six drug-metabolizing enzymes (CYP3A4, POR, uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), CYP1A2, CYP2C19, CYP2C9, and CYP2D6*10) in HepG2 (CYP2D6*10 KI-HepG2) cells to examine the effect of CYP2D6*10 on drug metabolism prediction. The protein expression levels of CYP2D6 in CYP2D6*10 KI-HepG2 cells were reduced relative to those in the CYP3A4-POR-UGT1A1-CYP1A2-CYP2C19-CYP2C9-CYP2D6 knock-in-HepG2 (CYPs-UGT1A1 KI-HepG2) cells. Consistent with the CYP2D6 protein expression results, CYP2D6 metabolic activity in CYP2D6*10 KI-HepG2 cells was reduced relative to CYPs-UGT1A1 KI-HepG2 cells. We successfully generated CYP2D6*10 KI-HepG2 cells with highly expressed, functional CYP2D6*10, as well as CYP1A2, 2C9, 2C19 and 3A4. CYP2D6*10 KI-HepG2 cells could be an invaluable model for hepatic metabolism and hepatotoxicity studies in East Asians, including Japanese.
Assuntos
Citocromo P-450 CYP2D6 , Hepatócitos , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Edição de Genes/métodos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Polimorfismo de Nucleotídeo Único , Modelos BiológicosRESUMO
BACKGROUND: Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2-negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. METHODS: In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). RESULTS: We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple-negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. CONCLUSION: This retrospective, real-world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes.
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias da Mama , Camptotecina , Progressão da Doença , Glucuronosiltransferase , Humanos , Feminino , Glucuronosiltransferase/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/efeitos adversos , Adulto , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Idoso , Polimorfismo Genético , Genótipo , ImunoconjugadosRESUMO
Jaundice affects almost all neonates in their first days of life and is caused by the accumulation of bilirubin. Although the core biochemistry of bilirubin metabolism is well understood, it is not clear why some neonates experience more severe jaundice and require treatment with phototherapy. Here, we present the first genome-wide association study of neonatal jaundice to date in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2000). The alternate allele of a common missense variant affecting the sequence of UGT1A4 reduces the susceptibility to jaundice five-fold, which replicated in separate cohorts of neonates of African American and European ancestries. eQTL colocalization analyses indicate that the association may be driven by regulation of UGT1A1 in the intestines, but not in the liver. Our results reveal marked differences in the genetic variants involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting distinct genetic mechanisms for the same biological pathways.
Assuntos
Bilirrubina , Estudo de Associação Genômica Ampla , Glucuronosiltransferase , Icterícia Neonatal , Humanos , Icterícia Neonatal/genética , Icterícia Neonatal/metabolismo , Bilirrubina/metabolismo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Recém-Nascido , Adulto , Feminino , Masculino , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Noruega , Locos de Características Quantitativas , Alelos , Mutação de Sentido Incorreto , Fígado/metabolismo , População Branca/genéticaRESUMO
Hepatic enzyme induction, an inherent defense system against xenobiotics, is known to simultaneously affect endocrine system functions in mammals under specific conditions, particularly thyroid hormone (TH) regulation. While this phenomenon has been studied extensively, the pathway leading to this indirect thyroid effect in mammals has unclear applicability to amphibians, despite the importance of amphibian species in assessing thyroid-disruptive chemicals. Here, we investigated the effects of three well-known mammalian enzyme inducers-ß-naphthoflavone (BNF), pregnenolone carbonitrile (PCN), and sodium phenobarbital (NaPB)-on the gene expression of phase-I and phase-II metabolizing enzymes in Xenopus laevis tadpoles. Waterborne exposure to BNF and PCN significantly induced the expression of both phase-I (cytochrome P450, CYP) and phase-II enzymes (UDP-glucuronosyltransferase, UGT and sulfotransferase, SULT), but in different patterns, while NaPB exposure induced CYP2B expression without affecting phase-II enzymes in tadpoles, in contrast to mammals. Furthermore, an ex vivo hepatic enzyme activity assay confirmed that BNF treatment significantly increased phase-II metabolic activity (glucuronidation and sulfation) toward TH. These results suggest the potential for certain mammalian enzyme inducers to influence TH clearance in X. laevis tadpoles. Our findings provide insights into the profiles of xenosensing activity and enzyme induction in amphibians, which can facilitate a better understanding of the mechanisms of indirect effects on the thyroid system via hepatic enzyme induction in nonmammalian species.
Assuntos
Sistema Enzimático do Citocromo P-450 , Larva , Fígado , Metamorfose Biológica , Hormônios Tireóideos , Xenopus laevis , beta-Naftoflavona , Animais , Larva/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Metamorfose Biológica/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , beta-Naftoflavona/farmacologia , beta-Naftoflavona/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/genética , Indução Enzimática/efeitos dos fármacos , Carbonitrila de Pregnenolona/farmacologia , Fenobarbital/farmacologia , Sulfotransferases/metabolismo , Sulfotransferases/genéticaRESUMO
Apple pomace is the residue left after apples are squeezed. The majority of pomace produced worldwide is produced by the apple manufacturing industry, however, most of the pomace produced by the industry is discarded. Apple pomace contains functional ingredients, such as polyphenols and triterpenoids, and exerts several beneficial effects on human health; however, studies on its cosmetic effects on the skin are lacking. Therefore, herein, we investigated the effects of apple pomace extract (APE) on human skin fibroblasts (HSFs) in vitro. When HSFs were cultured with the extract for 72 h, the number of HSFs increased at concentrations of 10 and 20 µg/mL. Transcriptome analysis and reverse transcription-quantitative PCR results revealed that the extract upregulated the expression of hyaluronan synthase (HAS) 1, HAS2, and HAS3 and downregulated the expression of HYAL1, a gene encoding the hyaluronan-degrading enzyme, in HSFs. Additionally, enzyme-linked immunosorbent assay revealed increased amounts of factors related to skin extracellular matrix, such as type I collagen and hyaluronic acid, secreted in the culture supernatant. The western blotting results suggested that the extract induced extracellular signal-regulated kinase and protein kinase B phosphorylation in HSFs. Additionally, several GO_Terms related to mitosis were detected in the Gene Ontology analysis. This is the first study to show that APE induces the proliferation of HSFs and production of factors related to skin anti-aging.
Assuntos
Proliferação de Células , Colágeno Tipo I , Fibroblastos , Hialuronan Sintases , Ácido Hialurônico , Malus , Extratos Vegetais , Pele , Humanos , Malus/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Ácido Hialurônico/metabolismo , Proliferação de Células/efeitos dos fármacos , Extratos Vegetais/farmacologia , Hialuronan Sintases/metabolismo , Hialuronan Sintases/genética , Pele/citologia , Pele/efeitos dos fármacos , Pele/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Células Cultivadas , Hialuronoglucosaminidase/metabolismo , Hialuronoglucosaminidase/genética , Fosforilação , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/genéticaRESUMO
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is one of the most prevalent and potent pulmonary carcinogens in tobacco products that increases the human lung cancer risk. Kava has the potential to reduce NNK and tobacco smoke-induced lung cancer risk by enhancing urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major metabolite of NNK) and thus reducing NNK-induced DNA damage. In this study, we quantified N-glucuronidated NNAL (NNAL-N-gluc), O-glucuronidated NNAL (NNAL-O-gluc), and free NNAL in the urine samples collected before and after 1-week kava dietary supplementation. The results showed that kava increased both NNAL-N-glucuronidation and O-glucuronidation. Since NNAL-N-glucuronidation is dominantly catalyzed by UGT2B10, its representative single-nucleotide polymorphisms (SNPs) were analyzed among the clinical trial participants. Individuals with any of the four analyzed SNPs appear to have a reduced basal capacity in NNAL-N-glucuronidation. Among these individuals, kava also resulted in a smaller extent of increases in NNAL-N-glucuronidation, suggesting that participants with those UGT2B10 SNPs may not benefit as much from kava with respect to enhancing NNAL-N-glucuronidation. In summary, our results provide further evidence that kava enhances NNAL urinary detoxification via an increase in both N-glucuronidation and O-glucuronidation. UGT2B10 genetic status has not only the potential to predict the basal capacity of the participants in NNAL-N-glucuronidation but also potentially the extent of kava benefits.
Assuntos
Carcinógenos , Suplementos Nutricionais , Glucuronídeos , Kava , Nitrosaminas , Humanos , Kava/química , Nitrosaminas/urina , Nitrosaminas/metabolismo , Carcinógenos/metabolismo , Glucuronídeos/urina , Masculino , Feminino , Neoplasias Pulmonares/induzido quimicamente , Pessoa de Meia-Idade , Piridinas/urina , Piridinas/química , Piridinas/administração & dosagem , Fumar/urina , Fumantes , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/genética , Adulto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The spectrum of UDP-glucuronosyltransferase (UGT1A1) variants, which are associated with Gilbert syndrome (GS) and Crigler-Najjar syndrome (CNS-II), has been reported in Chinese and western countries. However, the genotype-phenotype correlation of the individual UGT1A1 variants in GS and CNS-II remains to be clarified. To explore the UGT1A1 variant pattern and genotype-phenotype correlations, we enrolled 310 Chinese patients, including 232 patients with GS and 78 with CNS-II. Peripheral blood samples were collected for screening variants in the gene UGT1A1 by a polymerase chain reaction and Sanger sequencing. The correlation between different UGT1A1 variants and clinical phenotypes was analyzed. A total of 21 UGT1A1 variants were identified, including nine novel variants, and constituted 42 UGT1A1 genotypes in the GS and CNS-II patients. The most common UGT1A1 variants were A (TA)7TAA, p.G71R, p.Y486D, p.P364L, and p.P229Q, which were different from western countries. The p.Y486D variant had higher minor allele frequency in CNS-II than in GS whereas the A (TA)7TAA variant had higher minor allele frequency in GS than in CNS-II. The serum total bilirubin and triglyceride had significant differences among 14 recurrent genotypes of UGT1A1, in which the serum total bilirubin in patients with compound p.Y486D (homozygous)/p.G71R variant was significantly higher compared with homozygous A (TA)7TAA, homozygous p.G71R, compound heterozygous A (TA)7TAA/p.G71R and A (TA)7TAA/p.P364L, and combined heterozygous A (TA)7TAA/p.G71R/p.P229Q, while the serum triglyceride in patients with combined A (TA)7TAA (homozygous)/p.P229Q variant was significantly higher compared with compound heterozygous A (TA)7TAA/p.G71R, single heterozygous A (TA)7TAA, single heterozygous p.G71R, and homozygous A (TA)7TAA. The spectrum of UGT1A1 genotypes in Chinese patients was distinct from western countries. There were differential levels of serum total bilirubin and triglyceride in patients with recurrent genotypes of UGT1A1.
Assuntos
Síndrome de Crigler-Najjar , Doença de Gilbert , Glucuronosiltransferase , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Bilirrubina/sangue , China , Síndrome de Crigler-Najjar/genética , Síndrome de Crigler-Najjar/patologia , População do Leste Asiático/genética , Frequência do Gene , Estudos de Associação Genética , Genótipo , Doença de Gilbert/genética , Doença de Gilbert/sangue , Glucuronosiltransferase/genética , FenótipoRESUMO
This study aimed to evaluate the effects of UDP-glucuronosyltransferase (UGT) polymorphisms on mycophenolic acid (MPA) metabolism in renal transplant patients. A total of 11 single nucleotide polymorphisms (SNPs) of UGT1A1, UGT1A7, UGT1A8, UGT1A9, UGT1A10, and UGT2B7 were genotyped in 79 renal transplant patients. The associations of SNPs and clinical factors with dose-adjusted MPA area under the plasma concentration-time curve (AUC/D), the dose-adjusted plasma concentration (C0/D) of 7-O-MPA-glucuronide (MPAG), and the dose-adjusted plasma concentration (C0/D) of acyl MPAG (AcMPAG) were analyzed. In the univariate analysis, UGT1A1 rs4148323, age, and anion gap were associated with MPA AUC/D. MPA AUC/D was higher in patients with the GA genotype of UGT1A1 rs4148323 compared to patients with the GG genotype. UGT1A1 rs4148323, UGT1A9 rs2741049 and clinical factors, including age, serum total bilirubin, adenosine deaminase, anion gap, urea, and creatinine, were associated with MPAG C0/D. UGT2B7 rs7438135, UGT2B7 rs7439366, and UGT2B7 rs7662029 also were associated with AcMPAG C0/D. Multiple linear regression analysis showed that UGT1A9 rs2741049 and indirect bilirubin were negatively correlated with MPAG C0/D (P = .001; P = .039), and UGT2B7 rs7662029 was positively correlated with AcMPAG C0/D (P = .008). This study demonstrates a significant influence of UGT1A9 rs2741049 and UGT2B7 rs7662029 polymorphisms on the metabolism of MPA in vivo.
Assuntos
Glucuronosiltransferase , Transplante de Rim , Ácido Micofenólico , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Genótipo , Glucuronídeos/sangue , Glucuronosiltransferase/genética , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Imunossupressores/sangue , Ácido Micofenólico/farmacocinética , UDP-Glucuronosiltransferase 1ARESUMO
Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy.
Assuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Combinação de Medicamentos , Doença de Gilbert , Hiperbilirrubinemia , Indóis , Pirazóis , Piridinas , Quinolonas , Humanos , Doença de Gilbert/genética , Doença de Gilbert/tratamento farmacológico , Masculino , Aminofenóis/efeitos adversos , Aminofenóis/uso terapêutico , Feminino , Adulto , Fibrose Cística/tratamento farmacológico , Fibrose Cística/complicações , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Indóis/efeitos adversos , Benzodioxóis/efeitos adversos , Benzodioxóis/uso terapêutico , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Hiperbilirrubinemia/induzido quimicamente , Adulto Jovem , Pirróis/efeitos adversos , Adolescente , Glucuronosiltransferase/genética , Pirrolidinas , QuinolinasRESUMO
Gilbert syndrome is the most common hyperbilirubinemia, associated with a mutation in the UGT1A1 bilirubin gene, which produces an enzyme that conjugates bilirubin with glucuronic acid. Episodes of jaundice occurring in GS negatively affect patients' quality of life. This systematic review aimed to analyze clinical studies regarding nutrition in people with GS. The study followed the PRISMA guidelines and utilized the Ebsco, Embase, Cochrane, PubMed, Scopus, and Web of Science databases to search clinical trials focused on diet/nutrition in GS (1963-2023 years). The methodological quality of selected studies was assessed using the Jadad scale. As a result, 19 studies met the inclusion criteria. The research mainly focused on the impact of caloric restriction, consumption of various diet variants, and vegetables and fruits on hyperbilirubinemia and metabolic health. A nutritional intervention consisting of not applying excessive calorie restrictions and consuming fats and biologically active compounds in vegetables and fruits (Cruciferae, Apiaceous, Rutaceae) may prevent the occurrence of jaundice episodes. It is justified to conduct further research on detecting such compounds in food, which, by influencing the expression of the UGT liver enzyme gene, could contribute to regulating bilirubin concentration in the blood of people with GS.
Assuntos
Doença de Gilbert , Humanos , Doença de Gilbert/genética , Frutas , Verduras , Bilirrubina/sangue , Dieta/métodos , Ensaios Clínicos como Assunto , Glucuronosiltransferase/genética , Restrição Calórica/métodos , Estado Nutricional , Qualidade de VidaRESUMO
BACKGROUND: Lamotrigine as a broad-spectrum antiepileptic drug, is widely applied and its clinical efficacy is highly recognized. However, significant differences are observed in blood drug concentration of lamotrigine among individuals, which may have an impact on its efficacy. UGT1A4 is the main metabolic enzyme. However, it was inconsistent for the influence of UGT1A4 genetic polymorphism on concentration and efficacy of lamotrigine therapy. This study aimed to evaluate the influences of UGT1A4*3 genetic polymorphisms on lamotrigine concentration and therapeutic effect through meta-analysis. METHODS: The literature search was conducted in Medline, Embase, PubMed, Web of Science, Wan Fang Database, China National Knowledge Infrastructure, China Science and Technology Journal Database until January 2024. The primary outcome included the mean serum concentration, concentration-to-dose-ratio by body weight (CDR), or efficacy related to different UGT1A4*3 genotype for lamotrigine therapy. Data were collected to access the Mean Difference or odds ratio with 95% confidence interval. Meta-analysis was performed by RevMan 5.2. RESULTS: A total of eleven studies were enrolled. The meta-analysis for mean serum concentration of lamotrigine showed no significant difference between patients carrying TT genotypes and TG and GG genotypes group (MD: 0.12, 95% [-0.35, 0.58], P = 0.62). There was significant difference in CDR (MD: 0.49, 95% [0.03, 0.94], P = 0.04) and therapeutic efficacy (OR: 7.18, 95% [4.01, 12.83], P<0.00001) of lamotrigine, however no significant difference was found in subgroup analysis of CDR of children (MD: 0.03, 95% [-0.35, 0.42], P = 0.87) between patients carrying TT genotypes and TG and GG genotypes group. CONCLUSIONS: Polymorphism of UGT1A4*3 influenced the CDR and therapeutic efficacy of lamotrigine for antiepileptic therapy. Genotype analysis provided reference for personalized medication in the future. However, more high-quality evidences are necessary for precise and definitive conclusion.
Assuntos
Anticonvulsivantes , Epilepsia , Glucuronosiltransferase , Lamotrigina , Lamotrigina/uso terapêutico , Lamotrigina/sangue , Humanos , Glucuronosiltransferase/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/sangue , Anticonvulsivantes/uso terapêutico , Polimorfismo Genético , Genótipo , Polimorfismo de Nucleotídeo Único , Resultado do TratamentoRESUMO
BACKGROUND: Individual susceptibility to sodium valproate (VPA)-induced tremors may be due to genetic polymorphisms in the gene encoding the uridine diphosphate glucuronosyltransferase (UGT) enzyme, which affec the drug's clinical efficacy and cause toxic side effects. This study aimed to investigate the association between UGT1A6 polymorphisms and VPA-induced tremors in patients with epilepsy. METHODS: In total, 128 patients with epilepsy were enrolled. Patients with epilepsy who received VPA were divided into tremor and non-tremor groups. Polymerase chain reaction-restriction fragment length polymorphism was used to investigate the genotype of UGT1A6 polymorphisms. RESULTS: Carriers of the UGT1A6 A541G mutant genotype conferred a higher risk of tremor than wild-type carriers (odds ratio 2.128, P = 0.045). Logistic regression analysis showed that the A541G mutant genotype was a significant genetic risk factor for VPA-induced tremors. This suggests that individual susceptibility to VPA-induced tremors may result, at least partially, from genetic variation in UGT1A6 A541G. CONCLUSIONS: Patients with epilepsy carrying the UGT1A6 A541G mutant genotype may have VPA-induced tremors, and early detection of this genotype will help guide the clinical individualizsation of VPA treatment.
Assuntos
Anticonvulsivantes , Epilepsia , Glucuronosiltransferase , Tremor , Ácido Valproico , Humanos , Glucuronosiltransferase/genética , Ácido Valproico/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/genética , Masculino , Feminino , Tremor/genética , Tremor/induzido quimicamente , Anticonvulsivantes/efeitos adversos , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Adolescente , Genótipo , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Polimorfismo GenéticoRESUMO
This scoping review explores the impact of genetic polymorphisms on the pharmacokinetics and treatment responses of mycophenolic acid (MPA), an immunosuppressant. The study includes 83 articles from 1226 original studies, focusing on transplantation (n = 80) and autoimmune disorders (n = 3). Genetic variants in uridine 5'-diphospho-glucuronosyltransferase (UGT1A9, UGT1A8 and UGT2B7) and transmembrane transporters (ABCC2, SLCO1B1, SLCO1B3 and ABCB1) significantly affected MPA's pharmacokinetics and susceptibility to its adverse effect. Whereas variants in several genes including UGT1A9, UGT2B7, IMPDH1 and IMPDH2 have been associated with a higher risk of transplant rejection. However, there is a lack of studies on MPA's impact on autoimmune disorders and limited research on the Asian population. The findings underscore the need for further research on MPA's impact across different populations and diseases, particularly among other Asian ethnic groups, to advance personalized medicine in MPA therapy.
[Box: see text].
Assuntos
Glucuronosiltransferase , Imunossupressores , Proteína 2 Associada à Farmacorresistência Múltipla , Ácido Micofenólico , Humanos , Ácido Micofenólico/uso terapêutico , Ácido Micofenólico/farmacocinética , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Glucuronosiltransferase/genética , Polimorfismo Genético/genética , Rejeição de Enxerto/genética , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , IMP Desidrogenase/genética , UDP-Glucuronosiltransferase 1ARESUMO
Background and Objectives: Obesity is a major nutritional problem with an increasing prevalence among children and adolescents. The uridine-diphosphate-glucuronosyl-transferase1A1 (UGT1A1) gene encodes the UDP-glucuronosyl transferase enzyme, converting the toxic form of bilirubin to a soluble, nontoxic form. There are yet to be studies on the evaluation of the UGT1A1 variant types detected by next-generation sequencing (NGS) and their effects on bilirubin levels in nonsyndromic obese children. Methods: Forty-five children with body mass index (BMI) >95 percentile (p) constituted the obesity group and fourteen healthy children with BMI <85p constituted the control group. Anthropometric, clinical features, and biochemical parameters were evaluated. Furthermore, the UGT1A1 gene was sequenced by NGS. Results: The obese patients had lower total, direct, and indirect bilirubin levels (p = 0.422, 0.026, and 0.568, respectively). In addition, obese patients had more genetic variations in the UGT1A1 gene compared with the control group (62.2% and 50%, respectively). We found that children with variations had higher total direct and indirect bilirubin levels compared with those without variation (p = 0.016, 0.028, and 0.015, respectively). Children diagnosed with obesity in the first two years of their life had fewer genetic variations and lower total bilirubin levels (p = 0.000 and 0.013, respectively). Conclusions: It is assumed that bilirubin can be protective against many chronic diseases. Although bilirubin levels are found to be lower in obese children compared with the control group, some variations in the UGT1A1 gene may be supported by raising bilirubin. We suggest that high bilirubin levels caused by those UGT1A1 variations may be protective against obesity and its many negative effects.
Assuntos
Bilirrubina , Variação Genética , Glucuronosiltransferase , Sequenciamento de Nucleotídeos em Larga Escala , Obesidade , Humanos , Glucuronosiltransferase/genética , Criança , Feminino , Bilirrubina/sangue , Masculino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Obesidade/genética , Adolescente , Variação Genética/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Pré-Escolar , Obesidade Infantil/genética , Obesidade Infantil/sangueRESUMO
Uridine 5'-diphospho-glucuronosyltransferases (UGTs) demonstrate variable expression in the pediatric population. Thus, understanding of age-dependent maturation of UGTs is critical for accurate pediatric pharmacokinetics (PK) prediction of drugs that are susceptible for glucuronidation. Ontogeny functions of major UGTs have been previously developed and reported. However, those ontogeny functions are based on in vitro data (i.e., enzyme abundance, in vitro substrate activity, and so on) and therefore, may not translate to in vivo maturation of UGTs in the clinical setting. This report describes meta-analysis of the literature to develop and compare ontogeny functions for 8 primary UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) based on published in vitro and in vivo studies. Once integrated with physiologically based pharmacokinetics modeling models, in vivo activity-based ontogeny functions demonstrated somewhat greater prediction accuracy (mean squared error, MSE: 0.05) compared to in vitro activity (MSE: 0.104) and in vitro abundance-based ontogeny functions (MSE: 0.129).