Consumo de carnes e aminas heterocíclicas como fatores de risco para câncer / Meat and heterocyclic amines intake as risk factors for cancer

Introdução. O alto consumo de carne, principalmente vermelha e processada, tem sido relacionado com aumento de risco de doenças crônicas, especialmente o câncer. Uma das explicações possíveis são os métodos de preparo culinário a altas temperaturas, que acarretam na formação aminas heterocíclicas. Estes compostos são detoxificados no nosso organismo, passando por um processo, no qual podem ser geradas espécies reativas, relacionadas ao estresse oxidativo e ao dano ao DNA. Entretanto, os indivíduos apresentam respostas diferentes à mesma exposição dietética, podendo ter diferentes níveis de risco ou benefício com a mesma ingestão de alimentos. O código genético individual pode ser uma das causas dessa variação interpessoal. Objetivo. Investigar a relação entre o consumo de carnes e aminas heterocíclicas com estresse oxidativo e dano no DNA, considerando polimorfismos genéticos, fatores demográficos e de estilo de vida em residentes do Município de São Paulo. Métodos. Foram utilizados dados dietéticos, genéticos, bioquímicos e estilo de vida de um estudo transversal com amostra probabilística de múltiplo estágio chamado Inquérito de Saúde de São Paulo (ISACapital). Os dados de carne e aminas heterocíclicas foram obtidos a partir de um recordatório alimentar de 24 horas e questionário sobre métodos de cocção e graus de cozimento das carnes. A extração do DNA ocorreu pelo método por sal e utilizou-se a técnica PCR em tempo real para determinação dos seguintes polimorfismos de nucleotídeo único: CYP1A1 (rs1048943), CYP1A2 (rs762551, rs35694136), CYP1B1 (rs1056836, rs10012), NAT2 (rs1208, rs1041983, rs1799929, rs1801280, rs1799931, rs1799930, rs1801279), NAT1 (rs4986782, rs5030839, rs56379106, rs56318881, rs6586714), SULT1A1 (rs928286), UGT1A9 (rs3832043), SOD2 (rs4880), CAT (rs7943316), GSTA1 (rs3957357), GSTP1 (rs1695), e deleção dos genes GSTM1 e GSTT1. Foram utilizados os biomarcadores malonaldeído (MDA) no plasma para estimar o estresse oxidativo e o 8-OHdG no plasma para estimar dano ao DNA. As associações foram examinadas por meio de modelos de regressão múltipla linear e logística ajustadas por sexo, idade, IMC, consumo de frutas e calorias, atividade física e fumo. Resultados. O consumo médio de aminas heterocíclicas foi de 437ng/dia e a carne de boi foi a que mais contribuiu para o consumo de aminas. Participantes que consumiram carne de boi grelhada muito bem passada apresentaram maiores concentrações de MDA do que os demais. Encontrou-se associação positiva entre consumo de aminas heterocíclicas com estresse oxidativo e dano ao DNA, isto é, indivíduos que consumiram maiores teores de aminas heterocíclicas apresentaram maiores chances de ter elevados concentrações de MDA (OR=1,17; P=0,04) e maiores concentrações de 8-OHdG (=1,62; P=0,04). Observou-se também que esta associação pode ser modificada pelas características genéticas individuais, sendo que polimorfismos nos genes das enzimas de detoxificação NAT2 e CYP1B1 interagiram com o consumo de aminas, diminuindo o estresse oxidativo. Conclusão. Verificou-se que o alto consumo de aminas heterocíclicas contribuiu para maiores níveis de estresse oxidativo e dano ao DNA independente de fatores demográficos e de estilo de vida, aumentando o risco de doenças crônicas. Observou-se também que esta relação pode ser alterada na presença de polimorfismos genéticos individuais

Introduction. The excessive meat intake, especially red and processed meat, has been linked to chronic diseases, especially cancer. One of the reasons for that is the cooking process at high temperatures that can form heterocyclic amines (HCA). During HCA metabolism, reactive species can be formed, which can cause oxidative stress and DNA damage. However, people can show different answers to the same food intake, increasing or decreasing the risk of diseases. The DNA code can be one of the causes of this between-person variations. Objective. To investigate the association between meat/heterocyclic amine intake with oxidative stress and DNA damage, considering polymorphism, demographic and life style factors among population of São Paulo city. Methods. Information on food intake, genetics, biochemical, and lifestyle was obtained from a representative, multistage probability-based cross-sectional study titled Health Survey for Sao Paulo (ISA-Capital). Meat and heterocyclic amine intake was estimated by a 24-hour dietary recall complemented by a detailed questionnaire with preferences of cooking methods and level of doneness for meats. The salt method was used for DNA extraction and real time PCR to identify the following single nucleotide polymorphisms: CYP1A1 (rs1048943), CYP1A2 (rs762551, rs35694136), CYP1B1 (rs1056836, rs10012), NAT2 (rs1208, rs1041983, rs1799929, rs1801280, rs1799931, rs1799930, rs1801279), NAT1 (rs4986782, rs5030839, rs56379106, rs56318881, rs6586714), SULT1A1 (rs928286), UGT1A9 (rs3832043), SOD2 (rs4880), CAT (rs7943316), GSTA1 (rs3957357), GSTP1 (rs1695), GSTM1 and GSTT1 (null or not). We used malondialdehyde (MDA) concentration in plasma to estimated oxidative stress, and 8-OHdG concentration in plasma to estimate DNA damage. Analyses were performed using multivariate logistic and linear regressions adjusted for smoking, sex, age, body mass index, energy intake, fruit intake, smoking and physical activity. Results. Mean HCA intake was 437ng/day and beef was the meat that contributed more to HCA. Participants who consumed grilled beef very well-done presented more MDA concentration than other participants. We found significant association between heterocyclic amine intake with oxidative stress and DNA damage. Participants who consumed high levels of heterocyclic amines showed higher odds to show high MDA concentration (OR=1.17; P=0.04) and high 8-OHdG concentration (=1.62; P=0.04). These associations could be modified by individual genetic characteristics. Polymorphisms in genes that codify NAT2 and CYP1B1 detoxification enzymes interacted with HCA intake, decreasing oxidative stress. Conclusions. The high heterocyclic amine intake contributed to increase oxidative stress independently of lifestyle and demographic factors, increasing risk of chronic diseases. These relationships can be modified by genetic polymorphisms

Synthesis of novel coumarin derivatives bearing heterocyclic substituents for chemoprophylactic evaluation

A series of coumarin derivatives bearing heterocyclic substituents was synthesized. Bromination of the key compound 8-acetyl-7-hydroxy-4-methylcoumarin [I] under varied conditions gave the brominated derivatives II, III and IV, Conversions of III by several cyclocondensations gave the corresponding thiazole V, quinoxaline VI, quinoxalinone VIII and furanone IX derivatives. Also, methylation and cyclocondensation of the methylene-active acetyl groups of II with several aldehydes gave the corresponding pyridone various amines gave the corresponding amino side chains. Some of these newly synthesized products were studied for their chemoprophylatic effect on Schistosoma mansoni infected mice. Compound Xc a showed moderate effect

Synthesis and behaviour of a static benzoxazinone derivative towards nitrogen and sulphur nucleophieles

4 [H]-3,l-BENZOXAZIN-4-one derivatives bear saturated aliphatic substituents at position-2, [so called dynamic benzoxazinones], e.g., CH[3][1] C[3]H[7] [iso] [2], CH[2]COCH[3][3], CH2CN[4], C[3]H[7][n] and CH[2]CH[2]COOH[5] are among the more recent heterocyclic compounds. The electronically unsaturated character of these rings made difficult the synthesis of satisfactorily stable rings. New organic substituents with special properties in steric and in an electronic manner-helped to solve this problem. In the last two decades, our contribution to the solution of this problem includes the use of bulk substituents involving strong conjugation power [which so called static benzoxazinones[6-12]. In continuation of our recent article [1,3], on the behaviour of a static benzoxazinone derivative towards nitrogen and carbon nucleophiles, another derivative namely 2-[2-[4-bromohydroxyimmobenzyl] phenyl]-4[H]-3,l-benzoxazin-4-one [3] was obtained via the interaction of 1 - [4-bromophenyl] -4[H] -3,2 -benzoxazin-4-one [2] with anthranilic acid in boiling n-butanol in which hetero-ring opening takes place followed by cyclisation

Hidrolise do terconazol: relacao estrutura-atividade / Hydrolysis of terconazole: chemical structure - biological activity relationship

Com o objetivo de contribuir para melhor entendimento da relacao entre estrutura quimica e a atividade biologica do terconazol, foi proposta a otimizacao da sua hidrolise. O isolamento e identificacao de produto resultante, cujas analises levam a crer que se trata da 1-(2,4-diclorofenil)-2-(1H-1,2-4-triazol-1-il)etanona (DFTE), sugerem que o terconazol sofre hidrolise no anel 1,3-dioxolanico (cetal ciclico), resultando em composto carbonilico. A DFTE mostrou-se ativa contra Candida albicans CBS 3156 e Escherichia coli ATCC 25922, nao apresentando atividade contra Staphylococcus aureus ATCC 25923. Estes resultados confirmam dados sobre o mecanismo de acao do terconazol e de outros compostos azolicos, tanto contra fungos e leveduras como contra bacterias

Spectral, thermal and electrical characterization of Fe [II] 1,3 diphenyl-2-oximo-1,3 propandione with some heterocyclic bases

Iron [II] complexes of the type Fe [II] L2 B2 where L: 1,3 diphenyl 12-oximo- 1,3- propandione and B : pyridine, thiophene or furane, were synthesized and characterized by IR, DTA and electrical conductivity measurements. The presence of the respective heterocyclic bases help to stabilise the oxidation state of Fe [II] during its interaction with concerned oxime -1,3- diketone. The obtained data suggested the following descending order of relative thermal stability of the concerned adduct complexes. Fe [II] L[2] [Pyridine][2] > Fe [II] L[2] [Furane][2] > Fe [II] L[2] [Thiophene]. Furthermore, both of the thiophene and furane adduct complexes exhibited Semiconducting character in the temperature range 30-130 degree. Fe [II] L[2] [pyridine][2] showed such semiconducting behaviour only up to 90 degree. The calculated values of the activation energy of the electrical conductivity decreased in the following order: Fe [II] L[2] [Furane][2] > Fe [II] L[2] [Pyridine][2] > Fe [II] L[2] [Thiophene][2]

Conformational Equilibria in 1, 3-Azabicyclic Systems

La comparación de los parámetros de RMN'H para la perhidro-oxazolo (3,4-a) piridina (Jgem-2.5 Hz, delta4.40,3.81 ) con los 6-etilderivados 7 y 8, muestra la existencia de un equilibrio conformacional entre los conformadores trans-fusionado y el O-interno del cis-fusionado. La espectroscopia de RMN a bajas temperaturas permitió observar señales para ambos conformadores; y la integración de estas señales indican un equilibrio existente a 18ºK entre el 73 por ciento de 3-t y el 27 por ciento de 3-c

Heterocycles XIX Synthesis of substituted 2-pyridones

2-arylidene-1-indanones [1] and 2-arylidene-1-benzosuberones [II] were condensed with phenylacetamide in presence of a base to yield the corresponding 2-pyridones [III] and [IV] respectively. The structure of all products was substantiate be chemical and spectral methods