RESUMO
Citrus fruits and juices are a major source of dietary flavanones, and the regular consumption of these foods is inversely associated with the development of cardiometabolic diseases. However, the biological benefits depend on the bioavailability of these compounds, and previous studies have reported a large interindividual variability in the absorption and excretion of these compounds. Different factors, such as age, gender or genetic polymorphism of genes coding enzymes involved in the metabolism and transport of the flavanones, may explain this heterogeneity. This study aimed to assess the impact of single nucleotide polymorphism of sulfotransferases SULT1A1 and SULT1C4, and ABCC2 transporter genes on excretion of phase II flavanone metabolites in volunteers after 24 h of orange juice intake. Forty-six volunteers ingested a single dose of 500 mL of orange juice and 24-h urine was collected. The hesperetin and naringenin phase II metabolites were quantified in urine, and SNPs in SULT1A1, SULT1C4 and ABCC2 genes were genotyped. A significant (p < 0.05) relationship between the SNPs in these genes and the high excretion of phase II flavanone metabolites were observed. These results identified novel polymorphisms associated with higher absorption of flavanones, which may provide bases for future personalized nutritional guidelines for consuming flavanone-rich foods rich in these nutrients for better benefit from their health properties.
Assuntos
Citrus sinensis , Flavanonas , Hesperidina , Arilsulfotransferase/genética , Bebidas/análise , Citrus sinensis/genética , Humanos , Polimorfismo de Nucleotídeo Único , Sulfotransferases/genéticaAssuntos
Alopecia , Minoxidil , Sulfotransferases , Administração Oral , Alopecia/tratamento farmacológico , Alopecia/genética , Arilsulfotransferase/uso terapêutico , Feminino , Humanos , Minoxidil/uso terapêutico , Sulfotransferases/genética , Sulfotransferases/uso terapêutico , Resultado do TratamentoRESUMO
Based on observational studies, early age leukemia (EAL) was associated with maternal hormone exposure during pregnancy. We studied the association between genetic polymorphisms of estrogen metabolism and EAL. Using data from the Brazilian Collaborative Study Group of Infant Acute Leukemia (2000-2012), 350 cases and 404 age-matched controls and 134 mothers of cases and controls were genotyped to explore polymorphisms in genes of the estrogen metabolism pathway: CYP1B1 (c.1294C>G, rs1056836), CYP3A4 (c.-392A>G, rs2740574), CYP3A5 (c.219-237G>A, rs776746), GSTM1/GSTT1 deletions, and SULT1A1 (c.638G>A, rs9282861; and c.667A>G, rs1801030). Logistic regression was used to calculate the odds ratios (OR) with 95% confidence intervals (CIs), and unconditional logistic regression was used to estimate adjusted odds ratios (aORs) by ethnicity. Because of multiple testing, p values < 0.01 were significant after Bonferroni correction. SULT1A1 (c.638G>A) was associated to infant acute lymphoblastic leukemia and acute myeloid leukemia (AML) risk in males (additive model: aOR = 0.52; 95% CI: 0.29-0.95, p = 0.03; dominant model: aOR = 2.18; 95% CI: 1.17-4.05, p = 0.01, respectively). CYP1B1 polymorphism was associated with a decreased risk of AML either for non-white or female children (additive model: OR = 0.24; 95% CI: 0.08-0.76, p < 0.01; additive model: aOR = 0.27; 95% CI: 0.08-0.89, p = 0.03, respectively). Since polymorphisms of Cytochrome P450 genes presented gender-specific risk associations, we also investigated their expression. CYP1B1 was not expressed in 57.1% of EAL cases, and its expression varied by genotype, gender, and leukemia subtype. Maternal-fetal GSTT1 null genotype was associated with risk of EAL. This study shows that polymorphisms in genes of estrogen metabolism confer genetic susceptibility to EAL, mainly in males, and maternal susceptibility genes modify the risk for developing EAL in newborns.
Assuntos
Arilsulfotransferase/genética , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP3A/genética , Glutationa Transferase/genética , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Idade de Início , Brasil/etnologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Leucemia Mieloide Aguda/etnologia , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Fatores SexuaisRESUMO
Ethnic differences in patient genetics and breast cancer (BC) biology contribute to ethnic disparities in cancer presentation and patient outcome. We prospectively evaluated SNPs within phase I and phase II tamoxifen (TAM) metabolizing enzymes, and the estrogen receptor gene (ESR1), aiming to identify potential pharmacogenomic ethnicity patterns in an ER-positive BC cohort constituted of Hispanic and Non-Hispanic White (NHW) women in South Texas. Plasma concentrations of TAM/metabolites were measured using HPLC. CYP2C9, CYP2D6 and SULT1A1 genotypes were determined by DNA sequencing/Pyrosequencing technology. ESR1 PvuII and XbaI SNPs were genotyped using Applied Biosystems Taqman Allelic Discrimination Assay. Hispanics had higher levels of TAM, 4-hydroxytamoxifen, and endoxifen than NHWs. There was a higher prevalence of CYP2D6 EM within Hispanics than NHWs, which corresponded to higher endoxifen levels, but no differences were verified with regard to CYP2C9 and SULT1A1. We found a higher incidence of the wild type forms of the ESR1 in Hispanics than NHWs. The performance status, the disease stage at diagnosis, and the use of aromatase inhibitors might have overcome the overall favorable pharmacogenomics profile of Hispanics when compared to NHWs in relation to TAM therapy responsiveness. Our data strongly point to ethnical peculiarities related to pharmacogenomics and demographic features of TAM treated Hispanics and NHWs. In the era of pharmacogenomics and its ultimate goal of individualized, efficacious and safe therapy, cancer studies focused on the Hispanic population are warranted because this is the fastest growing major demographic group, and an understudied segment in the U.S.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/genética , Farmacogenética , Tamoxifeno/administração & dosagem , Idoso , Alelos , Arilsulfotransferase/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Feminino , Genótipo , Hispânico ou Latino , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tamoxifeno/efeitos adversos , Tamoxifeno/análogos & derivados , Tamoxifeno/metabolismoRESUMO
BACKGROUND: Estrogens influence many physiological processes including cardiovascular health. Polymorphisms in phase I and II estrogen metabolism enzymes are associated with lipid levels in women. METHODS: A cross-sectional study was carried out with 269 postmenopausal women, 116 who received oral hormonal therapy (HT) (39-75 years) with estrogens or estrogens plus progestagen, 153 that did not receive any HT (38-85 years), and 155 premenopausal women (18-52 years). Polymorphisms in UGT1A1 (rs5839491) and SULT1A1 (rs1042028) were analysed by PCR-based methods. Adjusted lipid levels means were compared among genotypes by one-way analysis of variance, with corrections for multiple testing. RESULTS: The UGT1A1*28 polymorphism was associated with total cholesterol (T-chol) (p = 0.030; corrected p = 0.060) and low-density lipoprotein cholesterol (LDL-C) levels (p = 0.011, corrected p = 0.022) in premenopausal women. The premenopausal and postmenopausal women, both carriers of SULT1A1*2/*2, had lower levels of T-chol and LDL-C means than carriers of the SULT1A1*1/*1 (p = 0.004, corrected p = 0.008 and 0.009, corrected p = 0.018, respectively). CONCLUSION: The data showed the presence of an association between the UGT1A1*28/*28 and SULT1A1*2/*2 and T-chol and LDL-C levels in women with different hormonal status. No previous studies investigated the association of the polymorphisms examined in this study with lipoprotein levels in women separately by hormonal status.
Assuntos
Arilsulfotransferase/genética , Glucuronosiltransferase/genética , Lipídeos/sangue , Polimorfismo Genético/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , DNA/análise , Terapia de Reposição de Estrogênios , Feminino , Frequência do Gene , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Pós-Menopausa , Pré-Menopausa , Triglicerídeos/sangueRESUMO
Cytosolic sulfotransferases are enzymes that catalyze the conjugation of sulfate groups to a variety of xenobiotic and endogenous substrates. A mutation in the SULT1A1 gene has been associated with decreased sulfotransferase activity. We studied 125 cancer patients and 100 healthy controls from Brazil matched by age and gender. The objective of this study was to assess the impact of the SULT1A1 polymorphism on sulfotransferase activity in a population of cancer patients. Both heterozygous and homozygous individuals for the mutant allele had significantly decreased sulfotransferase enzymatic activity. This decrease was more significant in cancer patients. The frequency of the SULT1A1( *)2 allele was increased in the myeloma group (odds ratio=0.53). These data suggest a functional role for the SULT1A1 gene polymorphism in cancer.
Assuntos
Arilsulfotransferase/genética , Neoplasias/genética , Polimorfismo Genético , Adulto , Idoso , Arilsulfotransferase/metabolismo , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Análise de Sequência de DNARESUMO
1. The Phase II in vitro metabolism of 3-methylindole (3MI) metabolites was investigated in pigs to determine the possible relationship between 3MI Phase II metabolism and 3MI accumulation in fat. Sulphation and glucuronidation of five of the seven major metabolites found to be produced by porcine microsomes was investigated using porcine cytosol and microsomes, respectively. The possible formation of glutathione conjugates was also investigated using microsomally activated 3MI intermediate(s). 2. No sulphation or glucuronidation was observed for metabolites 3-hydroxy-3-methyloxindole, 3-methyloxindole, indole-3-carbinol or 2-aminoacetophenone; however, 5-hydroxy-3-methylindole (5-OH-3MI) was conjugated with both sulphate and glucuronic acid. 3. The enzyme responsible for sulphation of 5-OH-3MI was identified as the thermostable form of phenol-sulphotransferase (TS-PST) based on its susceptibility to TS-PST inhibitors and the correlation between sulphation of 5-OH-3MI and sulphation of the prototype substrate p-nitrophenol (r = 0.94, p < 0.001). 4. A 3MI-glutathione adduct was identified in microsomal incubations containing 3MI and glutathione. 5. Sulphation of 5-OH-3MI was high in pigs with low levels of 3MI in fat. No relationship was observed between 3MI levels in fat and either glutathione transferase or glucuronidation activities in liver.
Assuntos
Arilsulfotransferase , Fígado/metabolismo , Escatol/metabolismo , Tecido Adiposo/química , Tecido Adiposo/metabolismo , Animais , Citosol/metabolismo , Inibidores Enzimáticos/farmacologia , Ácido Glucurônico/química , Ácido Glucurônico/metabolismo , Glutationa/química , Masculino , Microssomos Hepáticos/metabolismo , Nitrofenóis/metabolismo , Escatol/química , Sulfatos/química , Sulfatos/metabolismo , Sulfotransferases/antagonistas & inibidores , Sulfotransferases/metabolismo , SuínosRESUMO
Calophyllum brasiliense, Lonchocarpus oaxacensis, and Lonchocarpus guatemalensis are used in Latin American folk medicine. Four natural xanthones, an acetylated derivative, and two coumarins were obtained from C. brasiliense. Two flavanones were extracted from L. oaxacensis and one chalcone from L guatemalensis. These compounds were tested as substrates and inhibitors for two recombinant sulfotransferases (SULTs) involved in the metabolism of many endogenous compounds and foreign chemicals. Assays were performed using recombinant phenolsulfotransferase (SULT1A1) and hydroxysteroidsulfotransferase (SULT2A1). Three of the five xanthones, one of the flavonoids and the coumarins tested were substrates for SULT1A1. None of the xanthones or the flavonoids were sulfonated by SULT2A1, whereas the coumarin mammea A/BA was a substrate for this enzyme. The natural xanthones reversibly inhibited SULT1A1 with IC50 values ranging from 1.6 to 7 microM whereas much higher amounts of these compounds were required to inhibit SULT2A1 (IC50 values of 26-204 microM). The flavonoids inhibited SULT1A1 with IC50 values ranging from 9.5 to 101 microM, which compared with amounts needed to inhibit SULT2A1 (IC50 values of 11 to 101 microM). Both coumarins inhibited SULT1A1 with IC50 values of 47 and 185 pM, and SULT2A1 with IC50 values of 16 and 31 microM. The acetylated xanthone did not inhibit either SULT1AI or SULT2A1 activity. Rotenone from a commercial source had potency comparable to that of the flavonoids isolated from Lonchocarpus for inhibiting both SULTs. The potency of this inhibition depends on the position and number of hydroxyls. The results indicate that SULT1A1, but not SULT2A1, is highly sensitive to inhibition by xanthones. Conversely, SULT2A1 is 3-6 times more sensitive to coumarins than SULT1A1. The flavonoids are non-specific inhibitors of the two SULTs. Collectively, the results suggest that these types of natural products have the potential for important pharmacological and toxicological interactions at the level of phase-II metabolism via sulfotransferases.