[Show abstract][Hide abstract] ABSTRACT: Cardiovascular benefits from estradiol activation of nitric oxide endothelial production may depend on vascular wall and on estrogen receptor alpha (ESR1) and nitric oxide synthase (NOS3) polymorphisms. We have evaluated the microcirculation in vivo through nailfold videocapillaroscopy, before and after acute nasal estradiol administration at baseline and after increased sheer stress (postocclusive reactive hyperemia response) in 100 postmenopausal women, being 70 controls (healthy) and 30 simultaneously hypertensive and diabetic (HD), correlating their responses to PvuII and XbaI ESR1 polymorphisms and to VNTR, T-786C and G894T NOS3 variants. In HD women, C variant allele of ESR1 Pvull was associated to higher vasodilatation after estradiol (1.72 vs 1.64 mm/s, p = 0.01 compared to TT homozygotes) while G894T and T-786C NOS3 polymorphisms were connected to lower increment after shear stress (15% among wild type and 10% among variant alleles, p = 0.02 and 0.04). The G variant allele of ESR1 XbaI polymorphism was associated to higher HOMA-IR (3.54 vs. 1.64, p = 0.01) in HD and higher glucose levels in healthy women (91.8 vs. 87.1 mg/dl, p = 0.01), in which increased waist and HOMA-IR were also related to the G allele in NOS3 G894T (waist 93.5 vs 88.2 cm, p = 0.02; HOMA-IR 2.89 vs 1.48, p = 0.05). ESR1 Pvull, NOS3 G894T and T-786C polymorphism analysis may be considered in HD postmenopausal women for endothelial response prediction following estrogen therapy but were not discriminatory for endothelial response in healthy women. ESR1 XbaI and G894T NOS3 polymorphisms may be useful in accessing insulin resistance and type 2 diabetes risks in all women, even before menopause and occurrence of metabolic disease.
PLoS ONE 01/2014; 9(7):e103444. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of HPV in esophageal squamous cell carcinoma (ESCCs) is controversial. Therefore, we determined, through different methodologies, the prevalence of HPV in 264 ESCC samples from Brazil, and correlated it with the presence of surrogate markers and clinicopathological characteristics. HPV is present in 13% of ESCC, and with a 3-fold variation between high and medium incidence areas. Most HPV positive tumors were infected with HPV16, but this was not associated with p16 expression, TP53 mutation status, patient age, amount of tobacco or alcohol consumption, or overall survival. We conclude that HPV infection may not have a role in ESCC.
Cancer letters 07/2012; 326(1):52-8. · 5.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Esophageal cancer (EC) is among the 10 most common and fatal malignacies in the world, presenting a marked geographic variation in incidence rates between and within different countries. The TP53 tumor suppressor gene is highly mutated in esophageal tumors and its mutation pattern can offer clues to the etiopathology of the tumor. As Brazil presents one of the highest incidence areas in the West, a deeper knowledge of the molecular mechanisms related to EC development in the Brazilian population is needed. We analyzed the mutation profile of 110 esophageal squamous cell carcinomas (ESCC) of patients from Southeastern Brazil (Rio de Janeiro and São Paulo) and collected data regarding alcohol intake and tobacco smoking. We detected 41 mutations in tumor samples from 38 patients. There was no association between mutation frequency and tobacco smoking or alcohol drinking. The most frequently mutated codons were 179, 214, 220 and 248. Codons 179, 220 and 248 are hot-spots for ESCC, but codon 214 presents only 0.7% of the mutations registered in the IARC database. The mutation profile revealed a high percentage of mutations at A:T base pairs (34.1%) followed by deletions (17.1%). We concluded that the mutation profile detected in this study is different from that of patients from Southern Brazil but very similar to that previously seen in French patients, being characterized by a high frequency of mutations at A:T base pairs, which may be associated with acetaldehyde, the metabolic product of ethanol.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 11/2009; 696(1):10-5. · 3.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tobacco consumption is the main identifiable risk to cancer, contributing to the majority of tumors in upper aerodigestive tissues. The psychoactive compound responsible for tobacco addiction, nicotine and the potent carcinogens present at high concentrations either in cigarette mainstream smoke or in smokeless tobacco products, 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) and N-nitrosonornicotine (NNN) can be metabolized by CYP2A6. CYP2A6 is expressed in many aerodigestive tissues with high interindividual variability. The CYP2A6 gene is highly polymorphic and CYP2A6 alleles coding for enzymes with altered expression or metabolic capacity produce alterations in nicotine metabolism in vivo and seem to influence smoking behavior. These polymorphisms may change the rate of NNK and NNN activation and, therefore, may influence cancer risk associated with tobacco consumption. However, to date only a few and inconclusive studies have addressed the risk that a given CYP2A6 polymorphism presents for the development of tobacco-related tumors. Most, but not all, show a reduced risk associated with alleles that result in decreased enzyme activity. The overlapping substrate specificity and tissue expression between CYP2A6 and the highly similar CYP2A13 may add to the conflicting results observed. The intricate regulation of CYP2A6 and the variation of structurally different chemical compounds capable of inhibiting CYP2A enzymes also add to the complexity. Finally, the interaction between polymorphisms of genes that code for CYP2A6, CYP2A13 and other potent carcinogen-metabolizing CYP enzymes may help to determine individuals that are at higher risk of developing tumors associated with tobacco consumption.
[Show abstract][Hide abstract] ABSTRACT: CYP2A enzymes are responsible for nicotine metabolism and for activating tobacco-related carcinogens. Inhibition of CYP2A is a promising approach in chemoprevention, which could lead to a decrease in cigarette consumption and to a reduction in tobacco-related cancer risk. 8-Methoxypsoralen (8-MOP) is a mechanism-based inhibitor of human CYP2A6 and CYP2A13. 8-MOP is also an inhibitor of Cyp2a5, but the mode of this inhibition is unknown. There is no published data on the inhibition of CYP2A3 by 8-MOP. The objective of this work was to investigate the characteristics of 8-MOP inhibition on mouse hepatic Cyp2a5 and rat nasal CYP2A3, in order to determine the best experimental model for chemoprevention studies using 8-MOP. The results show that 8-MOP inhibits CYP2a5 through three different mechanisms: competitive, non-competitive (K(iu)=1.7 microM), and mechanism-based (K(inactivation) of 0.17 min(-1)). By contrast, 8-MOP was able to inhibit CYP2A3-mediated coumarin 7-hydroxylase only in a non-competitive way (K(iu)=0.22 microM). In conclusion, we showed that 8-MOP inhibits Cyp2a5 and CYP2A3 through different mechanisms.
Food and Chemical Toxicology 04/2008; 46(3):1190-5. · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Esophageal cancer is among the most common and fatal tumors in the world. Eighty percent of esophageal tumors are esophageal squamous cell carcinoma (ESCC). Brazil is one of the high incidence areas in the West, where tobacco and alcohol consumption have been associated with ESCC. However, polymorphisms in xenobiotic metabolizing genes may also contribute to the risk. Therefore, in this study, we analyzed the risk of ESCC associated with tobacco and alcohol consumption and with polymorphisms of CYP2A6 (CYP2A6*2), CYP2E1 (CYP2E1*5B, CYP2E1*6), GSTP1 (Ile105Val), GSTM1 and GSTT1 null genotypes in 126 cases and 252 age- and gender-matched controls. Data on the amount, length and type of tobacco and alcohol consumed were collected, and DNA was extracted from blood lymphocytes from all individuals. Polymorphisms were analyzed by polymerase chain reaction (PCR)-multiplex (GSTM1 and T1), PCR-Restriction Fragment Length Polymorphism (CYP2E1*5B and *6 and GSTP1 Ile105Val) or allele-specific PCR amplification (CYP2A6*2). Risks were evaluated by multivariate conditional regression analysis. As expected, tobacco [odds ratio (OR) = 6.71, 95% confidence interval (95% CI) 3.08-14.63] and alcohol (OR = 16.98, CI 7.8-36.98) consumption, independently or together (OR = 26.91, CI 13.39-54.05) were risk factors. GSTP1 Ile105Val polymorphism was an independent risk factor (OR = 2.12, CI 1.37-3.29), whereas GSTT1 wild-type was an independent protective factor for ESCC (OR = 0.37, CI 0.16-0.79). There was approximately 80% statistical power to detect both results. There was no risk associated with CYP2A6, CYP2E1 and GSTM1 polymorphisms. In conclusion, this study suggests an opposite role of GSTP1 and GSTT1 polymorphisms for the risk for ESCC.
[Show abstract][Hide abstract] ABSTRACT: Sugarcane workers in Brazil are exposed to various genotoxic compounds, including polycyclic aromatic hydrocarbons (PAHs), derived from an incomplete combustion process of burnt sugarcane fields. The effects of the occupational exposure to sugarcane fields burning were measured in urine samples of sugarcane workers from the northwest of the State of São Paulo when exposed (harvesting) and when non-exposed (non-harvesting). The urinary levels of 1-hydroxypyrene (1-OHP) and the influence of the genetic polymorphisms CYP1A1, GSTM1, GSTT1 and GSTP1 were evaluated. Our results showed that the 1-OHP levels were significantly higher (P<0.0000) in the exposed sugarcane workers (0.318 mumol mol(-1) creatinine) than in the non-exposed workers (0.035 mumol mol(-1) creatinine). In an unvaried analysis, no influence regarding the polymorphisms was observed. However, multivariate regression analysis showed that the CYP1A1()4 polymorphism in the exposed group, and age and the GSTP1 polymorphism in the non-exposed group significantly influenced urinary 1-OHP excretion levels (P<0.10). The same group of sugarcane workers was significantly more exposed to PAHs during the harvesting period than during the non-harvesting period.
Science of The Total Environment 11/2006; 370(2-3):382-90. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The toxicity that can result from the exposure to numerous xenobiotics can vary greatly for each individual. This is mainly due to differences in the activity of xenobiotic metabolizing enzymes (XME) that participate in the disposal of toxic xenobiotics from the human body. The genes that encode XMEs present a variety of polymorphisms that occur in the promoter or coding regions, resulting in differences in the amount or in the catalytic activities of the enzymes. Human populations differ regarding the frequency of alleles and haplotypes that are present in a given geographic region. Genetic background and ancestry are the main reasons for such variability. South America, due to an extensive colonization period, is populated by descendents of Amerindians, Africans and Europeans. The admixtures that happened in each country, however, vary according to historical and geographical conditions. Brazil, for example, has one of the world's most admixed populations with genetic contributions from several tribes of Amerindians, many still existent, from Africans, and from various waves of European immigrants. In this review we will discuss the frequency of genetic polymorphisms of XMEs, particularly Cytochrome P450s and Glutathione S-transferases, found in different populations of South American countries. The genetic background and degree of population admixture of each country is taken under consideration in a discussion of the difficulties generated by enzyme polymorphisms in the treatment of individuals within such populations.
[Show abstract][Hide abstract] ABSTRACT: Cytochrome P450 (CYP) is a superfamily of enzymes involved in the metabolism of endogenous compounds and xenobiotics. CYP2A6 catalyzes the oxidation of nicotine and the activation of carcinogens such as aflatoxin B1 and nitrosamines. CYP2E1 metabolizes ethanol and other low-molecular weight compounds and can also activate nitrosamines. The CYP2A6 and CYP2E1 genes are polymorphic, altering their catalytic activities and susceptibility to cancer and other diseases. A number of polymorphisms described are ethnic-dependent. In the present study, we determined the genotype and allele frequencies of the main CYP2A6 and CYP2E1 polymorphisms in a group of 289 volunteers recruited at the Central Laboratory of Hospital Universitário Pedro Ernesto. They had been residing in the city of Rio de Janeiro for at least 6 months and were divided into two groups according to skin color (white and non-white). The alleles were determined by allele specific PCR (CYP2A6) or by PCR-RFLP (CYP2E1). The frequencies of the CYP2A6*1B and CYP2A6*2 alleles were 0.29 and 0.02 for white individuals and 0.24 and 0.01 for non-white individuals, respectively. The CYP2A6*5 allele was not found in the population studied. Regarding the CYP2E1*5B allele, we found a frequency of 0.07 in white individuals, which was statistically different (P < 0.05) from that present in non-white individuals (0.03). CYP2E1*6 allele frequency was the same (0.08) in both groups. The frequencies of CYP2A6*1B, CYP2A6*2 and CYP2E1*6 alleles in Brazilians are similar to those found in Caucasians and African-Americans, but the frequency of the CYP2E1*5B allele is higher in Brazilians.
Brazilian Journal of Medical and Biological Research 02/2006; 39(2):195-201. · 1.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Esophageal cancer represents one of the most common and lethal cancers around the World. Some areas of South America, including parts of Brazil, present the highest incidence of the disease in the West. The main etiological factors that have been associated with the disease in Brazil are alcohol consumption, tobacco smoking and, in the South, consumption of hot maté. Nitrosamines are the only carcinogens capable of inducing tumors in the esophagus of experimental animals, with the rat being the most susceptible species, mainly due to tissue specific metabolic activation by CYP enzymes. Studies of CYP2A expression in the esophagus of rodents suggest an association between CYP2A expression and esophageal susceptibility to tumor induction. CYP2A6 and CYP2E1, the main enzymes to activate nitrosamines in humans, are the only carcinogen activating CYP enzymes to be expressed in the esophagus of Brazilians. Patients who presented high levels of CYP2A6 expression could activate nitrosamines at rates comparable to the rat. This expression profile is different from those present in French patients. We investigated 34 Brazilian patients regarding the risk associated with polymorphisms in drug metabolizing enzymes and TP53 mutations. A GSTP1 polymorphism presented a clear risk to white and non-white patients to develop esophageal cancer. GSTM1 null polymorphism also seemed to be associated with an increased risk. CYP2A6, CYP2E1, SOD2, and GSTT1 polymorphisms were not associated with an increased risk of esophageal cancer. TP53 mutations occurred mostly in exon 7, differing from the mutation profile found in the IARC database. The preliminary results obtained with polymorphisms of drug metabolizing enzymes and TP53 mutations need to be confirmed in a larger number of samples in order to compare the mechanisms of esophageal cancer development in Brazilians with that of other populations.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2003; 544(2-3):365-73. · 3.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The frequency of CYP1A1 (CYP1A1*2A), GSTM1, and GSTT1 polymorphisms, as well as the main risk factors associated with breast cancer were studied in Brazilian women, with malignant breast cancer (n=128), or age-matched controls (n=256). Only a family history of breast cancer presented a significant risk (OR=3.00, CI=1.27-7.06). Among non-whites, the CYP1A1*2A allele was underrepresented among patients. Statistical analysis indicated that this polymorphism may decrease the risk of breast cancer among these individuals, particularly after adjusting for the risk presented by selected risk factors (OR=0.30, 95% CI=0.12-0.76).
Cancer Letters 08/2002; 181(2):179-86. · 5.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The glutathione S-transferase (GST) family of enzymes has a vital role in phase II of biotransformation of environmental carcinogens, pollutants, drugs and other xenobiotics. GSTs are polymorphic, with the type and frequency of polymorphism being ethnic dependent. Polymorphisms in GST genes have been shown to be associated with susceptibility to disease and disease outcome. We determined the frequencies of GSTM1, GSTT1 and GSTP1 polymorphisms in 591 volunteers who had been residents of Rio de Janeiro for at least six months. Blood was collected and DNA extracted by proteinase K/SDS digestion. Information about social habits and health problems was also recorded. GSTM1 and GSTT1 polymorphisms were analyzed by a PCR-Multiplex procedure, whereas GSTP1 polymorphism was analyzed by PCR-RFLP. We found that 42.1% (48.9% of whites and 34.2% of non-whites) of the individuals had the GSTM1 null genotype, whereas 25.4% (25.1% of whites and 25.7% of non-whites) had the GSTT1 null genotype. The genotypic distribution of GSTP1 was 49.7% I/I, 38.1% I/V, and 12.2% V/V, whereas the allelic frequencies were 0.69 for the Ile allele, and 0.31 for the Val allele. The frequencies of GST polymorphisms in this Brazilian population were found to be different from those observed in other populations, particularly of other South American countries.