Luis Felipe Ribeiro Pinto

Brazilian National Cancer Institute, Rio de Janeiro, Rio de Janeiro, Brazil

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Publications (37)108.92 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on comparative genomic analysis of esophageal cancers: genomic polymorphisms, the genetic and epigenetic drivers in esophageal cancers, and the collection of data in the UK Barrett's Oesophagus Registry.
    Annals of the New York Academy of Sciences 09/2014; 1325(1). · 4.38 Impact Factor
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    ABSTRACT: One of the potential mechanisms of imatinib mesylate (IM) resistance in chronic myeloid leukemia (CML) is increased level of P-glycoprotein (Pgp). Pgp is an efflux pump capable of activating the multidrug resistance (MDR) phenotype. The gene encoding Pgp (ABCB1) has several binding sites in its promoter region, along with CpG islands and GC boxes, involved in its epigenetic control. In previous work, we performed a proteomic study to identify proteins involved in IM cross-resistance in acute leukemia. Among these proteins, we identified LRPPRC as a potential regulator of ABCB1 transcription via an invMED1 binding site in ABCB1. Interestingly, this invMED1 binding site overlaps with the GC -100 box. In this work, we investigated the potential role of LRPPRC in the regulation of ABCB1 transcriptional activity in CML resistance. In addition, we evaluated the potential connection between this regulation and the methylation status of the ABCB1 promoter in its GC -100 box. Our results show that LRPPRC binds prominently to the ABCB1 promoter in Lucena cells, an IM-resistant cell line. Luciferase assays showed that ABCB1 transcription is positively regulated by LRPPRC upon its knockdown. Pyrosequencing analysis showed that the ABCB1 promoter is differentially methylated at its GC -100 box in K562 cells compared with Lucena cells, and in CML patients with different response to IM. Chromatin immunoprecipitation and Pgp expression after DNA demethylation treatment showed that LRPPRC binding is affected by the methylation status of ABCB1 GC -100 box. Taken together, our findings indicate that LRPPRC is a transcription factor related to ABCB1 expression and highlight the importance of epigenetic regulation in CML resistance.
    Epigenetics 07/2014; 9(8):1172 - 1183. · 4.92 Impact Factor
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    ABSTRACT: The majority of endometrioid endometrial carcinomas (EEC) is diagnosed at stage I. Among these, 30% present myometrial invasion (stage IB), which is associated with tumor spread and relapse after primary treatment. Although an increased expression of RUNX1/AML1 and ERM/ETV5 in EEC have been suggested to be associated with early events of myometrial infiltration, there is no data regarding its expression along the evolution of EEC and possible associations with other clinicopathological parameters. Therefore, ERM/ETV5 and RUNX1/AML1 protein and gene expression profiles were assessed in different EEC stages to evaluate their role in endometrial carcinogenesis. RUNX1/AML1 and ERM/ETV5 proteins were analyzed by immunohistochemistry in 219 formalin fixed paraffin embedded endometrioid tumors and in 12 normal atrophic and proliferative endometrium samples. RUNX1/AML1 and ERM/ETV5 genes expression were analyzed by RT-qPCR. RUNX1/AML1 and ERM/ETV5 expression were decreased with increasing EEC stage, with a positive correlation between protein and gene expression for ERM/ETV5, but not for RUNX1/AML1. Both proteins were present in the nucleus of the tumor cells, whereas RUNX1/AML1, but not ERM/ETV5, was expressed in 7 out of 12 normal endometrial samples, with its expression being restricted to the cytoplasm of the positive cells. We concluded that there is a higher expression of ERM/ETV5 in early stages of EEC, whereas there seems to be a RUNX1/AML1 translocation from cytoplasm to nucleus in EEC neoplastic transformation.
    Cancer biology & therapy 04/2014; 15(7). · 3.29 Impact Factor
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    ABSTRACT: Esophageal cancer is one of the ten most frequent and fatal tumors worldwide and esophageal squamous cell carcinoma (ESCC) accounts for around 80% of the cases. The first symptoms of ESCC arise late during the progression of the disease and, therefore, the diagnosis is usually done in advanced stages. This leads to an inefficient treatment and consequently to a poor prognosis. Thus, a comprehensive knowledge of ESCC biology is of major importance to identify risk factors, especially in high incidence areas, and biomarkers which could enable ESCC prevention and interventions throughout the natural history of the disease. In this review, we present the current knowledge regarding ESCC etiology as well as the different genetic and epigenetic alterations already described in this tumor. We also discuss how these alterations could be used to anticipate ESCC diagnosis as well as how they can help improving treatment. A molecular natural history of the disease is proposed pointing out potential markers that may improve interventions at different points of ESCC development. Only when the different layers of complexity behind this tumor are elucidated, it will be possible to successfully perform prevention at different levels.
    Bioscience Reports 07/2013; · 1.88 Impact Factor
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    ABSTRACT: Agaricus brasiliensis currently is one of the most studied fungi because of its nutritional and therapeutic properties as an anti-inflammatory agent and an adjuvant in cancer chemotherapy. The effects of orally administered aqueous A. brasiliensis extract (14.3- and 42.9-mg doses) on parenchymal lung damage induced by carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were observed in Wistar rats. NNK treatment induced pulmonary inflammation, but not lung cancer, in the rats. The lungs of animals treated with NNK showed a higher level of inflammation than those of the control group according to histopathologic examinations (P < 0.01) and kurtosis analysis (P < 0.001) of a global histogram generated from thoracic computed tomography scans. There was no significant difference in the alveolar and bronchial exudates between animals treated with a 14.3-mg dose of A. brasiliensis extract and the control without NNK. However, a significant difference was found between animals treated with NNK, received a 42.9-mg dose of A. brasiliensis (P < 0.05), and the controls not treated with NNK. We did not observe a significant difference between the kurtoses of the A. brasiliensis (14.3 mg) and control groups. However, a 42.9-mg dose of A. brasiliensis resulted in lower kurtosis values than those observed in the control group (P < 0.001). In conclusion, a low dose of A. brasiliensis was more effective in attenuating pulmonary inflammation. Similar to the histopathological results, the computed tomography scans also showed a protective effect of A. brasiliensis at the lower dose, which prevented gross pulmonary consolidation.
    International Journal of Medicinal Mushrooms 01/2013; 15(4):345-355. · 0.84 Impact Factor
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    ABSTRACT: BACKGROUND: Esophageal squamous cell carcinoma (ESCC) shows a 5-year survival rate below 10%, demonstrating the urgency in improving its treatment. Alterations in epidermal growth factor receptors are closely related to malignancy transformation in a number of tumors and recent successful targeted therapies have been directed to these molecules. Therefore, in this study, we analyzed the expression of EGFR and HER2 and evaluated EGFR mutation profile as well as the presence of mutations in hotspots of KRAS and BRAF in ESCC patients. METHODS: We performed RT-qPCR, immunohistochemistry and Fluorescent in situ hybridization to determine EGFR and HER2 expression in ESCC patients, and direct sequencing and PCR-RFLP for mutations and polymorphism analysis. RESULTS: Our results showed an increased EGFR mRNA expression in tumors compared to surrounding tissue (p <0.05), with 11% of the cases presenting at least a four-fold difference between tumor and paired adjacent mucosa. EGFR protein overexpression was present only in 4% of the cases. The median expression of HER2 mRNA was not different between tumors and adjacent mucosa. Still, 7% of the tumors presented at least a 25-fold higher expression of this gene when compared to its paired counterpart. Immunohistochemical analysis revealed that 21% of the tumors were positive for HER2 (scores 2+ and 3+), although only 3+ tumors presented amplification of this gene. Mutation analysis for EGFR (exons 18-21), KRAS (codons 12 and 13) and BRAF (V600E) showed no mutations in any of the hotspots of these genes in almost 100 patients analyzed. EGFR presented synonymous polymorphisms at codon 836 (C>T) in 2.1% of the patients, and at codon 787 (G>A) in 79.2% of the cases. This last polymorphism was also evaluated in 304 healthy controls, which presented a similar frequency (73.7%) in comparison with ESCC patients. The absence of mutations of EGFR, KRAS and BRAF as well as the overexpression of EGFR and HER2 in less than 10% of the patients suggest that this signaling pathway is altered in only a small proportion of patients with ESCC. CONCLUSION: HER receptors target therapies may have the potential to be effective in only a minor fraction of patients with ESCC.
    BMC Cancer 12/2012; 12(1):569. · 3.33 Impact Factor
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    ABSTRACT: Thymine DNA glycosylase (TDG) belongs to the superfamily of uracil DNA glycosylases (UDG) and is the first enzyme in the base-excision repair pathway (BER) that removes thymine from G:T mismatches at CpG sites. This glycosylase activity has also been found to be critical for active demethylation of genes involved in embryonic development. Here we show that wild-type p53 transcriptionally regulates TDG expression. Chromatin immunoprecipitation (ChIP) and luciferase assays indicate that wild-type p53 binds to a domain of TDG promoter containing two p53 consensus response elements (p53RE) and activates its transcription. Next, we have used a panel of cell lines with different p53 status to demonstrate that TDG mRNA and protein expression levels are induced in a p53-dependent manner under different conditions. This panel includes isogenic breast and colorectal cancer cell lines with wild-type or inactive p53, esophageal squamous cell carcinoma cell lines lacking p53 or expressing a temperature-sensitive p53 mutant and normal human bronchial epithelial cells. Induction of TDG mRNA expression is accompanied by accumulation of TDG protein in both nucleus and cytoplasm, with nuclear re-localization occurring upon DNA damage in p53-competent, but not -incompetent, cells. These observations suggest a role for p53 activity in TDG nuclear translocation. Overall, our results show that TDG expression is directly regulated by p53, suggesting that loss of p53 function may affect processes mediated by TDG, thus negatively impacting on genetic and epigenetic stability.
    Cell cycle (Georgetown, Tex.) 11/2012; 11(24). · 5.24 Impact Factor
  • Vagner Bernardo, Luis Felipe Ribeiro Pinto, Rodolpho Mattos Albano
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    ABSTRACT: Reverse transcription followed by real-time PCR (RT-qPCR) is the gold standard for quantifying gene expression. However, because of PCR detection limits, theorized to be three template copies, the quantitation of genes exhibiting great expression variability is challenging. Using genes with high to low expression in rat tissues we experimentally demonstrated this limit and found it to be applicable only for describing reactions in which stochastic events and the Monte Carlo effect are present. We also determined the lower limits of RNA input that should be used to prevent artifactual template quantitation and we propose a methodology to assess RT-qPCR detection limits in any qPCR platform.
    Analytical Biochemistry 09/2012; · 2.58 Impact Factor
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    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
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    ABSTRACT: Cancers of the upper aerodigestive tract (UADT) are common forms of malignancy associated with tobacco and alcohol exposures, although human papillomavirus and nutritional deficiency are also important risk factors. While somatically acquired DNA methylation changes have been associated with UADT cancers, what triggers these events and precise epigenetic targets are poorly understood. In this study, we applied quantitative profiling of DNA methylation states in a panel of cancer-associated genes to a case-control study of UADT cancers. Our analyses revealed a high frequency of aberrant hypermethylation of several genes, including MYOD1, CHRNA3 and MTHFR in UADT tumors, whereas CDKN2A was moderately hypermethylated. Among differentially methylated genes, we identified a new gene (the nicotinic acetycholine receptor gene) as target of aberrant hypermethylation in UADT cancers, suggesting that epigenetic deregulation of nicotinic acetycholine receptors in non-neuronal tissues may promote the development of UADT cancers. Importantly, we found that sex and age is strongly associated with the methylation states, whereas tobacco smoking and alcohol intake may also influence the methylation levels in specific genes. This study identifies aberrant DNA methylation patterns in UADT cancers and suggests a potential mechanism by which environmental factors may deregulate key cellular genes involved in tumor suppression and contribute to UADT cancers.
    Epigenetics: official journal of the DNA Methylation Society 03/2012; 7(3):270-7. · 4.58 Impact Factor
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    ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is believed to arise from esophageal mucosa through accumulation of both genetic and epigenetic changes. DNA methylation is a critical epigenetic mechanism involved in key cellular processes and its deregulation has been linked to many human cancers, including ESCC. The aim of this study is to examine the global deregulation of methylation states in ESCC and identify potential early biomarkers. With this purpose, we performed a bead array analysis of more than 800 cancer-related genes in ten ESCC samples, ten matched surrounding tissues and four esophageal mucosa from healthy individuals. Pyrosequencing was used for validation of DNA methylation changes in up to 106 cases and 27 controls. A total of 37 CpG sites were found to be differentially methylated between tumors and surrounding tissues. These CpG sites were significantly enriched in genes related to several pathways including IL-10 anti-inflammatory signaling pathway and cell communication pathway. In addition, by comparing with healthy esophageal mucosa, we identified TFF1 gene as a potential early marker of ESCC. This is the first study to address methylation changes in ESCC in a large set of genes. Methylome analysis is shown as a sensitive and powerful tool to identify molecular players in ESCC. These data should prove to be the reference for future studies identifying potential biomarkers and molecular targets in ESCC.
    Epigenetics: official journal of the DNA Methylation Society 10/2011; 6(10):1217-27. · 4.58 Impact Factor
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    ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is highly fatal due to late diagnosis and inefficient treatment. Early disease detection could improve diagnosis and patient survival. Esophageal squamous epithelial cells express SPRR3, a member of the small proline-rich protein family, which is downregulated in ESCC. Therefore, SPRR3 expression may be used as a biomarker to follow the transition from healthy mucosa to ESCC. Both SPRR3 mRNA splice variants, v1 and v2, were evaluated by real time PCR in tumor and histologically normal adjacent tissue biopsies from 84 ESCC patients and 18 healthy controls. SPRR3-v1 was most highly expressed in the esophageal mucosa of healthy subjects, with an increasingly lower expression in the adjacent mucosa of ESCC patients and in tumors, respectively. SPRR3-v2 expression was low in normal mucosa and in tumors but it was higher in the adjacent mucosa of ESCC patients. In addition, we found a significant correlation between a lower SPRR3-v1 and SPRR3-v2 expression and age and alcohol consumption, respectively. SPRR3 protein expression presented a good correlation with SPRR3 mRNA expression. Cut-off points to discriminate between healthy mucosa, tumor and adjacent mucosa were determined with receiver operating characteristic (ROC) curves. This analysis showed that SPRR3-v1 expression discriminates the esophageal mucosa of healthy subjects from the adjacent mucosa and the tumor of ESCC patients with high sensitivity and specificity. Our data shows that the quantitative analysis of SPRR3 mRNA is a robust and reliable method to monitor the malignant transformation of the healthy esophageal mucosa into ESCC.
    Experimental and Molecular Pathology 07/2011; 91(2):584-9. · 2.13 Impact Factor
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    ABSTRACT: Primary hepatocytes are widely used in investigating drug metabolism and its toxicological effects. N-Nitrosodiethylamine (NDEA)-induced genotoxicity and cytotoxicity was used in primary cultures of female rat hepatocytes in the presence of phenobarbital (PB). PB pre-treatment (1mM) increased the number of necrotic (2-fold) and apoptotic cells (4-fold) after NDEA treatment (0.21-105 μg/mL). The mitotic indices and the number of micronucleated cells decreased, thus suggesting cytotoxicity. An increased number of chromosomal aberrations were observed after pre-treatment with PB. NDEA-treatment (0.21-21 μg/mL) induced expression of the CYP2B1 and CYP2B2 mRNA and PB treatment alone induced ~6-fold and ~2-fold increases of CYP2B1 and CYP2B2 mRNA, respectively. NDEA treatment following PB exposure increased CYP2B1 mRNA expression under all tested concentrations and also increased CYP2B2 expression at 21 and 105 μg/mL. Our data suggest that the alteration of CYP2B1/2 expression by PB increased the cytotoxicity and genotoxicity of NDEA leading to the final genotoxic metabolite.
    Toxicology Letters 07/2011; 206(2):139-43. · 3.15 Impact Factor
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    ABSTRACT: In rats, N-nitrosodiethylamine (NDEA) induces tumors mainly in the liver. This could be because various enzymes are responsible for the metabolic activation of NDEA, besides the hepatic NDEA metabolizing enzyme, CYP2E1. We examined NDEA genotoxicity and cytotoxicity in primary cultures of female rat hepatocytes; we also looked at how it affected CYP mRNA expression. Single incubation with 0.9% NaCl resulted in a mean of 0.2% apoptotic cells, which doubled with 105 μg NDEA/mL. The frequency of necrosis with NDEA treatment was also doubled. Besides the cytotoxic effects, there was also a 4-fold decrease in mitotic index and a 3-fold decrease in the percentage of cells with micronuclei. A significant increase in micronucleus cells when hepatocytes were incubated with 2.1 μg NDEA/mL suggests that DNA repair was inactive. The chromosomal aberration evaluation revealed a discrete dose-response curve. Treatment with NDEA induced increases in CYP mRNA: CYP2B2 (1.8 times) and CYP2E1 (1.6 times) with non-cytotoxic NDEA concentrations (0.21-21 μg/mL). CYP2B1 mRNA levels decreased at 0.21 μg NDEA/mL (2.5-fold), while CYP4A3 mRNA decreased 1.3-fold. NDEA treatment at 2.1 μg/ mL induced a 1.9-fold increase in CYP3A1 mRNA. Understanding the cumulative effects in target cells during precarcinogenesis is crucial to understanding the mode of action of potential carcinogens and in order to develop comprehensive chemical toxicity profiles.
    Genetics and molecular research: GMR 01/2011; 10(4):2340-8. · 0.99 Impact Factor
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    ABSTRACT: To study the expression of heme-oxygenase-1 (HO-1), an enzyme induced by oxidative stress, in specimens obtained from an experimental model in rats that evaluated the role of gastric and duodenal reflux in esophageal carcinogenesis. Esophageal specimens embedded in paraffin obtained from different experimental groups of rats were used for immunohistochemistry analysis of HO-1 expression. The rats had been divided into the following groups and were killed after 22 weeks: (1) cardioplasty to induce acid reflux; (2) esophagoduodenal anastomosis to induce duodenal reflux; (3) no treatment; (4) cardioplasty + diethylnitrosamine (DEN); (5) esophagoduodenal anastomosis + DEN; and (6) DEN. The study sample comprised 3 specimens from each group with the most severe histopathological lesions found on each study branch. The expression of HO-1 was seen only in rat specimens submitted to esophagoduodenal anastomosis (Groups 2 and 5), and the analysis of mean fluorescence intensity revealed a significant increase of HO-1 expression (4.8 and 4.6 fold, respectively) when compared with the control group (Group 3) (p<0.05). The main target for HO-1 induction was the inflammatory cells inside the tumor or in subepithelial areas. Rats exposed to gastric reflux had no HO-1 expression. Reflux esophagitis induced by reflux of duodenal contents, which provoked considerable oxidative stress, may play an important role in esophageal carcinogenesis. Acid reflux did not induce oxidative stress in this experimental model.
    Acta cirurgica brasileira / Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia 06/2010; 25(3):304-10. · 0.48 Impact Factor
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    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
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    ABSTRACT: It has been suggested that the blood clotting initiator protein, tissue factor (TF), participates in tumor growth, metastasis and angiogenesis. In addition, a family of G protein-coupled-receptors known as protease-activated receptors (PARs) has also been implicated in tumor biology. These receptors might be activated by blood coagulation proteases thus eliciting a number of pro-tumoral responses, including the expression of interleukin-8 (IL-8). Therefore, in this study we analyzed the expression of TF, PAR-1, PAR-2 and IL-8 genes in patients with esophageal cancer, one of the most aggressive neoplastic diseases. Total RNA was extracted from tissue samples (tumor and the corresponding normal mucosa) obtained from patients submitted to esophagectomy or endoscopy and further analyzed by semi-quantitative reverse transcriptase-polymerase (RT-PCR) and/or real-time quantitative PCR (qPCR). Expression of full-length transmembrane TF was significantly higher in tumor samples whereas no differences were observed in alternatively spliced TF transcripts. Tumor tissue showed increased mRNA levels for PAR-1 but not PAR-2. Remarkably, IL-8 expression was not detected in most normal tissues but showed very high expression in tumor samples. As expected, qPCR revealed greater differences in the expression pattern of all transcripts analyzed but the general profile was very similar to that observed by RT-PCR. Altogether our data suggest a possible role for blood clotting proteins in the biology of human esophageal cancer.
    Oncology Reports 07/2009; 21(6):1599-604. · 2.30 Impact Factor
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    Genetics and Molecular Research - GENET MOL RES. 01/2009; 8(2):782-782.
  • Sílvia Visoni, Matti Lang, Luis Felipe Ribeiro Pinto
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    ABSTRACT: Nitrosamines are carcinogens that require metabolic activation by CYP enzymes in order to exert their carcinogenic effect. Species differences exist in their esophageal carcinogenic potency, with the rat being the most sensitive and the Syrian hamster a resistant species. In the latter, the liver is the main target organ. This difference does not apply to directly acting N-nitroso compounds, suggesting that tissue-specific metabolic activation is involved in hamster esophageal resistance to nitrosamines. We have previously shown that Cytochrome P450 2A3 (CYP2A3) is responsible for N-nitrosodiethylamine activation in the rat esophagus. In order to find a mechanistic explanation for the resistance of hamster esophagus for nitrosamines, we have compared the metabolism of NDEA between esophagus and liver of the hamster.Hamster esophagus is capable of activating NDEA (Km = 1.02 ± 0.44 μM and Vmax = 1.96 ± 0.26 nmol acetaldehyde/min/mg microsomal protein). However, the hamster liver showed a 40-fold higher catalytic efficiency (Vmax/Km) towards NDEA metabolism compared with its esophagus. Hamster esophagus expresses CYP2A8, CYP2A9 and CYP2A16, but not CYP2E1. An antibody against human CYP2A6 was able to inhibit NDEA metabolism in hamster esophageal, but not liver microsomes.Our results suggest that in the hamster esophagus, but not in the liver, most of the NDEA is metabolized by CYP2A enzymes, but with a rather poor efficiency when compared to the liver. This is in accordance with previous results showing that for the hamster, the main target organ of NDEA is the liver.
    Toxicology Letters 12/2008; 183(s 1–3):90–94. · 3.15 Impact Factor
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    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.
    Pharmacogenomics 12/2008; 9(11):1737-52. · 3.86 Impact Factor

Publication Stats

337 Citations
108.92 Total Impact Points

Institutions

  • 2012
    • Brazilian National Cancer Institute
      • Division of Pathological Anatomy
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 2001–2012
    • Rio de Janeiro State University
      • • Departamento de Biofísica e Biometria (DBB)
      • • Departamento de Bioquímica (DBq)
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 2009
    • CEP America
      Emeryville, California, United States
  • 2002
    • Universidade Federal Fluminense
      • Departamento de Biologia Celular e Molecular (GCM)
      Niterói, Rio de Janeiro, Brazil