O câncer é a segunda maior causa de morte no Brasil, atrás apenas de doenças cardíacas. Por isto, é evidente que grandes recursos sejam direcionados para a pesquisa no descobrimento de novas opções com a finalidade de erradicar esta doença. Dentre estas opções, a quimioprevenção do câncer tem chamado a atenção já que, mesmo com os imensos avanços no conhecimento sobre os mecanismos da carcinogênese e conseqüente desenvolvimento de novas drogas, os dados estatísticos de mortalidade não se tornaram menores. Somando-se a estes fatos, deve ser considerado que no Brasil o tratamento padrão do câncer não chega a todas as pessoas por ser extremamente caro. Desta forma, a quimioprevenção do câncer com fatores presentes na dieta ou oriundos de fontes consideradas baratas como fitoterápicos, deve ser apreciada. Assim, este trabalho teve como objetivo avaliar os efeitos quimiopreventivos e antineoplásicos de uma planta brasileira, o guaraná (Paullinia cupana Mart var. sorbilis). Foram utilizados alguns experimentos em camundongos como indução genotóxica em fígado pela Dietilnitrosamina (DEN); carcinogênese pulmonar induzida pela 4-(metilnitrosamino)-1-(3-piridil)-1-butanona (NNK), uma nitrosamina presente no tabaco; tumor ascítico de Ehrlich; disseminação hematógena de melanoma B16/f10; e cultivo de células tumorais e não tumorais. Além disso, caracterizou-se o papel da Conexin43 na carcinogênese pulmonar induzida pelo NNK e os efeitos do guaraná sobre o receptor CAR e sua ação quando da administração do ligante do CAR, 1,4-bis[2-(3,5-dichloropiridiloxi)]benzeno (TCPOBOP). Pudemos observar efeitos quimiopreventivos e antineoplásicos do guaraná dependendo do modelo utilizado, demonstrando que seu modo de ação principal é a redução da proliferação celular. Além disso, observamos que os tumores de pulmão dos animais tratados com a planta apresentavam menor tamanho, menor grau maligno, menor índice de proliferação celular e menor ativação do fator de transcrição CREB. Observamos também que a Conexina43 (Cx43) tem importante papel na carcinogênese pulmonar induzida pelo NNK, atuando como supressor tumoral e em fases tardias possivelmente tendo papel inverso, ou seja, como um oncogene. Caracterizamos os efeitos do guaraná sobre a ativação do receptor CAR e demonstramos que, por si só, o guaraná induz a expressão do CAR, além de alterar a expressão de alguns de seus transcritos como a CYP2B10 e CYP3A11. Ao analisarmos os efeitos de extratos de guaraná sobre células de tumor de pulmão (E9) in vitro, verificamos o mesmo efeito antiproliferativo, diminuindo a expressão do PCNA e da Conexina43 de maneira dose-dependente, além de verificar um aumento da expressão do receptor CAR. Ao fim propomos uma hipótese de mecanismo de ação baseando-se nas alterações encontradas oriundas da administração do guaraná. Concluímos que o guaraná apresenta componentes com ação antitumoral em camundongos, tendo efeito quimiopreventivo ou antineoplásico dependendo do modelo utilizado. / Cancer is the second biggest cause of deaths in Brazil, only behind of cardiac diseases. As a result, it is evident that great resources for research will be directed towards the discovery of new options to eradicate this disease. Among these options, cancer chemoprevention has calling for attention since the huge advances in the knowledge of carcinogenesis and development of new drugs did not decrease statistical data on mortality due to cancer. In addition, it must be considered that in Brazil, cancer therapy is not available for all given that it is too expensive. Therefore, cancer chemoprevention with dietary factors or from medicinal plants has got to be treasured. Following these lines, the aim of this work was to evaluate the chemopreventive and antineoplastic effects of a Brazilian plant, Paullinia cupana Mart var. sorbilis, most known as guarana. It was used several experiments in mice and cell culture essays as: protection against DEN-induced DNA damage; NNK-induced lung carcinogenesis; Ehrlich Ascitic Tumor; metastasis of B16/f10 melanoma cells; and cell culture of a tumorigenic and a non-tumorigenic cell lines. Additionally, it was characterized the role of Connexin43 in the NNK-induced lung carcinogenesis and the effects of guarana on the CAR receptor before and after the administration of TCPOBOP. We note a chemopreventive or antineoplastic effect of guarana depending on the model employed and showed that the mode of action responsible for these effects was reduced cell proliferation. Also, the lung tumors of guarana-treated animals were smaller, less aggressive, with decreased cell proliferation and CREB activation. On the other hand, we observed that Connexin43 have an important role on NNK-induced lung carcinogenesis because it may act as a tumor suppressor and in advanced stages as an oncogene. The effects of guarana on the CAR activation were characterized and we showed that guarana induces CAR mRNA expression, altering the levels of its transcripts as CYP2B10 and CYP3A11. We also examined the effects of guarana extracts on a lung tumor cell culture (E9 cells) and demonstrated the same antiproliferative effect observed previously, by decreased PCNA and Connexin43 proteins in a dose-dependent manner along with an increase in CAR protein. At last we hypothesized a mechanism of action for guarana effects basing in our findings. We concluded that guarana presents substances that have antitumoral effects in mice, enclosing a chemopreventive or antineoplastic effect depending on the model studied.

<p>This investigation focused on the mRNA expression of drug metabolising Cytochromes P-450 (CYP) and UDP-glucuronosyltransferases (UGT) and the transport protein P-glycoprotein (Pgp) in the small intestine of humans and rats.</p><p>The mRNA expression of the investigated genes in the human small intestine (duodenum) varies between individuals giving each one of us personal profile. In general, the most dominant forms are Pgp, CYPs 2C9, 2D6, 3A4, and UGTs 1A1, 1A10, 2B7. However, which of these is the highest expressed one varies between individuals.</p><p>The correlation in expression between some CYP forms and UGT forms respectively is relatively high, which indicates that they have some regulatory mechanisms in common. It was also shown that the mRNA expression of both CYPs and UGTs may be affected by endogenous and exogenous factors. Sex and ethnic background, affected the mRNA expression of CYP2A6 and 2E1 respectively. Commonly used drugs such as acetylsalicylicacid (ASA) and omeprazole (omep) affect CYP2A6, CYP2E1 (ASA) and CYP3A4, UGT1A4 (omep). The expression of UGT1A4 is also affected by smoking. All these factors are commonly used and can therefore lead to important drug-drug interactions.</p><p>It was also shown that the human small intestinal CYP mRNA expression pattern differs from that found in the rat. The rat CYP expression is rather constant between the different individuals, and the main rat intestinal forms are CYP1A1, CYP2C, CYP2D6 and CYP3A1. The expression is the same for females and males and no difference can be seen between the different segments of the rat small intestine. As metabolic studies have often been done with rat liver we compared the mRNA expression in the two organs. We found that the mRNA expression of 1A1 was absent in the liver and that the CYP2B1, CYP2Cs, CYP2D1 and Pgp all had a stronger mRNA expression in the small intestine compared to the liver. It is therefore important to realise that results from metabolic studies on liver may not be directly extrapolated to the small intestine.</p><p>Artemisinin is an orally used drug in multidrug treatment of malaria in Southeast Asia. It has been suggested that artemisinin can induce drug metabolism and therefore be involved in drug-drug interactions. This study shows that artemisinin induces mainly the CYP2B via nuclear receptor CAR.</p>

This investigation focused on the mRNA expression of drug metabolising Cytochromes P-450 (CYP) and UDP-glucuronosyltransferases (UGT) and the transport protein P-glycoprotein (Pgp) in the small intestine of humans and rats. The mRNA expression of the investigated genes in the human small intestine (duodenum) varies between individuals giving each one of us personal profile. In general, the most dominant forms are Pgp, CYPs 2C9, 2D6, 3A4, and UGTs 1A1, 1A10, 2B7. However, which of these is the highest expressed one varies between individuals. The correlation in expression between some CYP forms and UGT forms respectively is relatively high, which indicates that they have some regulatory mechanisms in common. It was also shown that the mRNA expression of both CYPs and UGTs may be affected by endogenous and exogenous factors. Sex and ethnic background, affected the mRNA expression of CYP2A6 and 2E1 respectively. Commonly used drugs such as acetylsalicylicacid (ASA) and omeprazole (omep) affect CYP2A6, CYP2E1 (ASA) and CYP3A4, UGT1A4 (omep). The expression of UGT1A4 is also affected by smoking. All these factors are commonly used and can therefore lead to important drug-drug interactions. It was also shown that the human small intestinal CYP mRNA expression pattern differs from that found in the rat. The rat CYP expression is rather constant between the different individuals, and the main rat intestinal forms are CYP1A1, CYP2C, CYP2D6 and CYP3A1. The expression is the same for females and males and no difference can be seen between the different segments of the rat small intestine. As metabolic studies have often been done with rat liver we compared the mRNA expression in the two organs. We found that the mRNA expression of 1A1 was absent in the liver and that the CYP2B1, CYP2Cs, CYP2D1 and Pgp all had a stronger mRNA expression in the small intestine compared to the liver. It is therefore important to realise that results from metabolic studies on liver may not be directly extrapolated to the small intestine. Artemisinin is an orally used drug in multidrug treatment of malaria in Southeast Asia. It has been suggested that artemisinin can induce drug metabolism and therefore be involved in drug-drug interactions. This study shows that artemisinin induces mainly the CYP2B via nuclear receptor CAR.

O câncer é a segunda maior causa de morte no Brasil, atrás apenas de doenças cardíacas. Por isto, é evidente que grandes recursos sejam direcionados para a pesquisa no descobrimento de novas opções com a finalidade de erradicar esta doença. Dentre estas opções, a quimioprevenção do câncer tem chamado a atenção já que, mesmo com os imensos avanços no conhecimento sobre os mecanismos da carcinogênese e conseqüente desenvolvimento de novas drogas, os dados estatísticos de mortalidade não se tornaram menores. Somando-se a estes fatos, deve ser considerado que no Brasil o tratamento padrão do câncer não chega a todas as pessoas por ser extremamente caro. Desta forma, a quimioprevenção do câncer com fatores presentes na dieta ou oriundos de fontes consideradas baratas como fitoterápicos, deve ser apreciada. Assim, este trabalho teve como objetivo avaliar os efeitos quimiopreventivos e antineoplásicos de uma planta brasileira, o guaraná (Paullinia cupana Mart var. sorbilis). Foram utilizados alguns experimentos em camundongos como indução genotóxica em fígado pela Dietilnitrosamina (DEN); carcinogênese pulmonar induzida pela 4-(metilnitrosamino)-1-(3-piridil)-1-butanona (NNK), uma nitrosamina presente no tabaco; tumor ascítico de Ehrlich; disseminação hematógena de melanoma B16/f10; e cultivo de células tumorais e não tumorais. Além disso, caracterizou-se o papel da Conexin43 na carcinogênese pulmonar induzida pelo NNK e os efeitos do guaraná sobre o receptor CAR e sua ação quando da administração do ligante do CAR, 1,4-bis[2-(3,5-dichloropiridiloxi)]benzeno (TCPOBOP). Pudemos observar efeitos quimiopreventivos e antineoplásicos do guaraná dependendo do modelo utilizado, demonstrando que seu modo de ação principal é a redução da proliferação celular. Além disso, observamos que os tumores de pulmão dos animais tratados com a planta apresentavam menor tamanho, menor grau maligno, menor índice de proliferação celular e menor ativação do fator de transcrição CREB. Observamos também que a Conexina43 (Cx43) tem importante papel na carcinogênese pulmonar induzida pelo NNK, atuando como supressor tumoral e em fases tardias possivelmente tendo papel inverso, ou seja, como um oncogene. Caracterizamos os efeitos do guaraná sobre a ativação do receptor CAR e demonstramos que, por si só, o guaraná induz a expressão do CAR, além de alterar a expressão de alguns de seus transcritos como a CYP2B10 e CYP3A11. Ao analisarmos os efeitos de extratos de guaraná sobre células de tumor de pulmão (E9) in vitro, verificamos o mesmo efeito antiproliferativo, diminuindo a expressão do PCNA e da Conexina43 de maneira dose-dependente, além de verificar um aumento da expressão do receptor CAR. Ao fim propomos uma hipótese de mecanismo de ação baseando-se nas alterações encontradas oriundas da administração do guaraná. Concluímos que o guaraná apresenta componentes com ação antitumoral em camundongos, tendo efeito quimiopreventivo ou antineoplásico dependendo do modelo utilizado. / Cancer is the second biggest cause of deaths in Brazil, only behind of cardiac diseases. As a result, it is evident that great resources for research will be directed towards the discovery of new options to eradicate this disease. Among these options, cancer chemoprevention has calling for attention since the huge advances in the knowledge of carcinogenesis and development of new drugs did not decrease statistical data on mortality due to cancer. In addition, it must be considered that in Brazil, cancer therapy is not available for all given that it is too expensive. Therefore, cancer chemoprevention with dietary factors or from medicinal plants has got to be treasured. Following these lines, the aim of this work was to evaluate the chemopreventive and antineoplastic effects of a Brazilian plant, Paullinia cupana Mart var. sorbilis, most known as guarana. It was used several experiments in mice and cell culture essays as: protection against DEN-induced DNA damage; NNK-induced lung carcinogenesis; Ehrlich Ascitic Tumor; metastasis of B16/f10 melanoma cells; and cell culture of a tumorigenic and a non-tumorigenic cell lines. Additionally, it was characterized the role of Connexin43 in the NNK-induced lung carcinogenesis and the effects of guarana on the CAR receptor before and after the administration of TCPOBOP. We note a chemopreventive or antineoplastic effect of guarana depending on the model employed and showed that the mode of action responsible for these effects was reduced cell proliferation. Also, the lung tumors of guarana-treated animals were smaller, less aggressive, with decreased cell proliferation and CREB activation. On the other hand, we observed that Connexin43 have an important role on NNK-induced lung carcinogenesis because it may act as a tumor suppressor and in advanced stages as an oncogene. The effects of guarana on the CAR activation were characterized and we showed that guarana induces CAR mRNA expression, altering the levels of its transcripts as CYP2B10 and CYP3A11. We also examined the effects of guarana extracts on a lung tumor cell culture (E9 cells) and demonstrated the same antiproliferative effect observed previously, by decreased PCNA and Connexin43 proteins in a dose-dependent manner along with an increase in CAR protein. At last we hypothesized a mechanism of action for guarana effects basing in our findings. We concluded that guarana presents substances that have antitumoral effects in mice, enclosing a chemopreventive or antineoplastic effect depending on the model studied.