Busca avançada
Ano de início
Entree
(Referência obtida automaticamente do Google Scholar, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Cytotoxicity Mechanism of Two Naphthoquinones (Menadione and Plumbagin) in Saccharomyces cerevisiae

Texto completo
Autor(es):
Vieira Castro, Frederico Augusto [1] ; Mariani, Diana [1] ; Panek, Anita Dolly [1] ; Araujo Eleutherio, Elis Cristina [1] ; Pereira, Marcos Dias [1]
Número total de Autores: 5
Afiliação do(s) autor(es):
[1] Univ Fed Rio de Janeiro, Inst Quim, Dept Bioquim, LIFE, Rio De Janeiro - Brazil
Número total de Afiliações: 1
Tipo de documento: Artigo Científico
Fonte: PLoS One; v. 3, n. 12, p. e3999, 2008.
Citações Web of Science: 71
Resumo

Background: Quinones are compounds extensively used in studies of oxidative stress due to their role in plants as chemicals for defense. These compounds are of great interest for pharmacologists and scientists, in general, because several cancer chemotherapeutic agents contain the quinone nucleus. However, due to differences in structures and diverse pharmacological effects, the exact toxicity mechanisms exerted by quinones are far from elucidatation. Methodology/Principal Findings: Using Saccharomyces cerevisiae, we evaluated the main mechanisms of toxicity of two naphthoquinones, menadione and plumbagin, by determining tolerance and oxidative stress biomarkers such as GSH and GSSG, lipid peroxidation levels, as well as aconitase activity. The importance of glutathione transferases (GST) in quinone detoxification was also addressed. The GSSG/GSH ratio showed that menadione seemed to exert its toxicity mainly through the generation of ROS while plumbagin acted as an electrophile reacting with GSH. However, the results showed that, even by different pathways, both drugs were capable of generating oxidative stress through their toxic effects. Our results showed that the control strain, BY4741, and the glutathione transferase deficient strains (gtt1 Delta and gtt2 Delta) were sensitive to both compounds. With respect to the role of GST isoforms in cellular protection against quinone toxicity, we observed that the Gtt2 deficient strain was unable to overcome lipid peroxidation, even after a plumbagin pre-treatment, indicating that this treatment did not improve tolerance when compared with the wild type strain. Cross-tolerance experiments confirmed distinct cytotoxicity mechanisms for these naphthoquinones since only a pre-treatment with menadione was able to induce acquisition of tolerance against stress with plumbagin. Conclusions/Significance: These results suggest different responses to menadione and plumbagin which could be due to the fact that these compounds use different mechanisms to exert their toxicity. In addition, the Gtt2 isoform seemed to act as a general protective factor involved in quinone detoxification. (AU)

Processo FAPESP: 04/10067-6 - Estresse, transporte e metabolismo de alfa-glicosídios em Saccharomyces cerevisiae
Beneficiário:Pedro Soares de Araujo
Modalidade de apoio: Auxílio à Pesquisa - Temático