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Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiae.
PLoS One. 2008; 3(12):e3999.Plos

Abstract

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 (gtt1Delta and gtt2Delta) 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.

Authors+Show Affiliations

Departamento de Bioquímica, Laboratório de Investigação de Fatores de Estresse, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil. fredcastro@iq.ufrj.brNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19098979

Citation

Castro, Frederico Augusto Vieira, et al. "Cytotoxicity Mechanism of Two Naphthoquinones (menadione and Plumbagin) in Saccharomyces Cerevisiae." PloS One, vol. 3, no. 12, 2008, pp. e3999.
Castro FA, Mariani D, Panek AD, et al. Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiae. PLoS One. 2008;3(12):e3999.
Castro, F. A., Mariani, D., Panek, A. D., Eleutherio, E. C., & Pereira, M. D. (2008). Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiae. PloS One, 3(12), e3999. https://doi.org/10.1371/journal.pone.0003999
Castro FA, et al. Cytotoxicity Mechanism of Two Naphthoquinones (menadione and Plumbagin) in Saccharomyces Cerevisiae. PLoS One. 2008;3(12):e3999. PubMed PMID: 19098979.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiae. AU - Castro,Frederico Augusto Vieira, AU - Mariani,Diana, AU - Panek,Anita Dolly, AU - Eleutherio,Elis Cristina Araújo, AU - Pereira,Marcos Dias, Y1 - 2008/12/22/ PY - 2008/06/09/received PY - 2008/11/10/accepted PY - 2008/12/23/entrez PY - 2008/12/23/pubmed PY - 2009/6/10/medline SP - e3999 EP - e3999 JF - PloS one JO - PLoS One VL - 3 IS - 12 N2 - 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 (gtt1Delta and gtt2Delta) 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/19098979/Cytotoxicity_mechanism_of_two_naphthoquinones__menadione_and_plumbagin__in_Saccharomyces_cerevisiae_ L2 - https://dx.plos.org/10.1371/journal.pone.0003999 DB - PRIME DP - Unbound Medicine ER -