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1.
Article in English | MEDLINE | ID: mdl-27476330

ABSTRACT

Several studies have reported that guanylhydrazones display a variety of desirable biological properties, such as antihypertensive, antibacterial, and antimalarial behaviour. They furthermore promote anti-pneumocystosis and anti-trypanosomiasis, exhibit antitumor activity, and show significant cytotoxicity against cancer cell lines. In this work, we have evaluated the cytotoxicity, mutagenicity, and genotoxicity of two guanylhydrazones derivatives, (E)-2-[(2,3-dimethoxyphenyl) methylene] hydrazine carboxymidamide hydrochloride (2,3-DMeB) and (E)-2-[(3,4-dimethoxyphenyl) methylene] hydrazine carboxymidamide hydrochloride (3,4-DMeB), in different biological models. Both 2,3-DMeB and 3,4-DMeB induce weak cytotoxic and mutagenic effects in bacteria and yeast. The genotoxicity of these compounds was determined in a fibroblast cell line (V79) using alkaline comet assay, as well as a modified comet assay with bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (EndoIII). Both guanylhydrazone derivatives induced DNA damage. Treatment of V79 cells with EndoIII and FPG proteins demonstrated a significant effect of 2,3-DMeB and 3,4-DMeB with respect to oxidized bases. In addition, the derivatives induced a significant increase in the frequency of micronucleated cells at high doses. The antifungal and anti-trypanosomal properties of these guanylhydrazone derivatives were also evaluated, and the obtained results suggest that 2,3-DMeB is more effective than 3,4-DMeB. The biological activity of 2,3-DMeB and 3,4-DMeB may thus be related, at least in part, to their oxidative potential, as well as to their ability to interact with DNA. Considering the previously reported in vitro antitumor activity of guanylhydrazone derivatives in combination with the lack of acute toxicity and the fact that DNA damage is only observed at high doses should render both compounds good candidates for in vivo studies on antitumor activity.


Subject(s)
DNA Damage/drug effects , Hydrazones/toxicity , Mutagens/toxicity , Animals , Antifungal Agents/toxicity , Cell Line , Comet Assay , Cricetulus , Humans , Lipid Peroxidation/drug effects , Mutagenicity Tests , Trypanocidal Agents/toxicity , Trypanosoma cruzi/drug effects
2.
Article in English | MEDLINE | ID: mdl-24561378

ABSTRACT

The organoselenium compound, dicholesteroyl diselenide (DCDS) is a structural analogue of diphenyl diselenide (DPDS) and may be considered as a promising antioxidant drug in vivo. Nevertheless, little is known about the toxicological properties of DCDS. In the present study we evaluated the cytotoxic, genotoxic and mutagenic properties of DCDS in Chinese hamster lung fibroblasts (V79) and in strains of the yeast Saccharomyces cerevisiae, proficient and deficient in several DNA-repair pathways. The results with V79 cells show that DCDS induced cytotoxicity, GSH depletion and elevation of lipid peroxidation at lower concentrations than did DPDS. DCDS also generated single- and double-strand DNA breaks in V79 cells, both in the presence and in the absence of metabolic activation, as revealed by alkaline and neutral comet assays. Moreover, the induction of oxidative DNA base-damage was demonstrated by means of a modified comet assay with formamidopyrimidine-DNA glycosylase and endonuclease III. Treatment with DCDS also induced micronucleus formation in V79 cells as well as point and frame-shift mutations in a haploid wild-type strain of S. cerevisiae. Yeast mutants defective in base excision-repair proteins were the most sensitive to DCDS. Pre-incubation with N-acetylcysteine reduced DCDS's oxidative, genotoxic and mutagenic effects in yeast and in V79 cells. Our findings indicate that the presence of cholesteroyl substituents in DCDS results in elevation of its cytotoxic and genotoxic potential compared with that of DPDS in yeast and in V79 cells. However, due to dose-dependent contrasting behaviour of organoselenium compounds and differences in their toxicity in in vitro and in vivo systems, further studies are needed in order to establish the non-toxic concentration range for treatment in mammals.


Subject(s)
Cholesterol/analogs & derivatives , DNA Damage , Micronuclei, Chromosome-Defective/chemically induced , Mutagens/toxicity , Organoselenium Compounds/toxicity , Saccharomyces cerevisiae/drug effects , Animals , Biomarkers/analysis , Cell Line , Cell Survival/drug effects , Cholesterol/toxicity , Comet Assay , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Frameshift Mutation/drug effects , Humans , Lipid Peroxidation/drug effects , Micronucleus Tests , Oxidative Stress/drug effects , Saccharomyces cerevisiae/genetics , Toxicity Tests/methods
3.
Rev Soc Bras Med Trop ; 45(3): 395-8, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22760144

ABSTRACT

INTRODUCTION: This study analyzed the occurrence and the contamination of triatomines by trypanosomatids in Orbignya speciosa (babassu) specimens in the State of Rondônia, Brazil, in two different environments (pasture and woods). METHODS: Capture of triatomines on babassus and microscopic search for trypanosomatids in their digestive tube were carried out. RESULTS: Four hundred ninety-four (494) specimens were captured (Rhodnius prolixus and R.robustus), of which 35.6% of the triatomines were positive for trypanosomatids. CONCLUSIONS: The high index of natural infection along with the abundance of triatomines points out to the necessity to create an epidemiological surveillance system to monitor vector-borne transmission and deepen the studies on the ecology of such vectors in the Amazon.


Subject(s)
Insect Vectors/parasitology , Rhodnius/parasitology , Trypanosomatina/isolation & purification , Animals , Arecaceae/parasitology , Brazil , Chagas Disease/transmission , Insect Vectors/classification , Population Density , Rhodnius/classification
4.
Rev. Soc. Bras. Med. Trop ; 45(3): 395-398, May-June 2012. ilus, graf, map, tab
Article in English | LILACS | ID: biblio-1288065

ABSTRACT

INTRODUCTION: This study analyzed the occurrence and the contamination of triatomines by trypanosomatids in Orbignya speciosa (babassu) specimens in the State of Rondônia, Brazil, in two different environments (pasture and woods). METHODS: Capture of triatomines on babassus and microscopic search for trypanosomatids in their digestive tube were carried out. RESULTS: Four hundred ninety-four (494) specimens were captured (Rhodnius prolixus and R.robustus), of which 35.6% of the triatomines were positive for trypanosomatids. CONCLUSIONS: The high index of natural infection along with the abundance of triatomines points out to the necessity to create an epidemiological surveillance system to monitor vector-borne transmission and deepen the studies on the ecology of such vectors in the Amazon.


INTRODUÇÃO: O estudo analisou a ocorrência e o índice de contaminação por tripanosomatídeos de triatomíneos em Orbynia speciosa no Estado de Rondônia, Brasil, em 2 ambientes (pastagem e floresta). MÉTODOS: Captura em palmeiras e esfregaços do conteúdo do tubo digestivo dos triatomíneos analisados por microscopia óptica. RESULTADOS: Capturaram-se 494 espécimes (Rhodnius prolixus e R. robustus), sendo que 35,6% dos triatomíneos estavam positivos para tripanosomatídeos. CONCLUSÕES: O elevado índice de infecção natural, aliados à abundância de triatomíneos, mostram a necessidade de se criar um sistema de vigilância epidemiológica para monitorar a transmissão vetorial e aprofundar estudos sobre a ecologia destes vetores na Amazônia.


Subject(s)
Animals , Rhodnius/parasitology , Trypanosomatina/isolation & purification , Insect Vectors/parasitology , Rhodnius/classification , Brazil , Population Density , Chagas Disease/transmission , Arecaceae/parasitology , Insect Vectors/classification
5.
Food Chem Toxicol ; 50(10): 3548-55, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22222931

ABSTRACT

Patulin, a known mycotoxin, is considered a significant contaminant in apples, apple-derived products and feeds. This study investigated the genotoxic effects of patulin in multiple organs (brain, kidney, liver and urinary bladder) of mice using an in vivo comet assay. We assessed the mechanism underlying this genotoxicity by measuring the GSH content and the thiobarbituric acid-reactive species (TBARS) level. Male CF-1 mice were given 1.0-3.75 mg/kg patulin intraperitoneally. The effect of patulin was dose-dependent and the highest patulin dose induced DNA strand breaks in the brain (damage index, DI, in hippocampus increased from 36.2 in control animals to 127.5), liver (44.3-138.4) and kidneys (31.5-99); decreased levels of GSH (hippocampus--from 46.9 to 18.4 nmol/mg protein); and an increase in lipid peroxidation (hippocampus--from 5.8 to 20.3 MDA equivalents/mg protein). This finding establishes an interrelationship between the pro-oxidant and genotoxic effects of patulin. Pre-treatment administration of N-acetyl-cysteine reduced patulin-induced DNA damage (hippocampus--DI from 127.5 to 39.8) and lipid peroxidation (hippocampus--20.3 to 12.8 MDA equivalents/mg protein) by restoring cellular GSH levels, reinforcing the positive relationship between patulin-induced GSH depletion and DNA damage caused by systemic administration of this mycotoxin.


Subject(s)
DNA Damage/drug effects , Patulin/toxicity , Acetylcysteine/pharmacology , Animals , Comet Assay , Dose-Response Relationship, Drug , Glutathione/metabolism , Hippocampus/drug effects , Kidney/drug effects , Male , Mice , Molecular Structure , Oxidative Stress , Patulin/administration & dosage , Patulin/chemistry
6.
Rev Soc Bras Med Trop ; 44(4): 511-2, 2011.
Article in English | MEDLINE | ID: mdl-21860901

ABSTRACT

INTRODUCTION: This paper reports, for the first time, the presence of the Eratyrus mucronatus species in the State of Rondonia, Brazil. METHODS: These specimens were caught by chance in the forest and later they were collected using luminous traps. RESULTS: After finding these specimens, the number of the Triatominae genera in Rondonia rose to four, while its species rose to seven. CONCLUSIONS: Complimentary studies will be conducted in order to allow for clearer understanding the ecology of this arthropod, its possible role in transmitting Chagas' disease and its current geographical distribution.


Subject(s)
Insect Vectors/classification , Triatominae/classification , Animals , Brazil , Chagas Disease/transmission
7.
Rev. Soc. Bras. Med. Trop ; 44(4): 511-512, July-Aug. 2011. ilus
Article in English | LILACS | ID: lil-596604

ABSTRACT

INTRODUCTION: This paper reports, for the first time, the presence of the Eratyrus mucronatus species in the State of Rondonia, Brazil. METHODS: These specimens were caught by chance in the forest and later they were collected using luminous traps. RESULTS: After finding these specimens, the number of the Triatominae genera in Rondonia rose to four, while its species rose to seven. CONCLUSIONS: Complimentary studies will be conducted in order to allow for clearer understanding the ecology of this arthropod, its possible role in transmitting Chagas' disease and its current geographical distribution.


INTRODUÇÃO: O presente comunicado relata pela primeira vez a ocorrência da espécie Eratyrus mucronatus, no Estado de Rondônia. MÉTODOS: Os espécimes foram coletados ao acaso na mata e depois com a ajuda de armadilhas luminosas. RESULTADOS: Com o encontro dos espécimes, o registro de gêneros de triatomíneos em Rondônia passa para quatro e o de espécies para sete. CONCLUSÕES: Estudos complementares serão realizados para compreender melhor a ecologia do artrópodo, seu eventual papel da transmissão da doença de Chagas e sua real distribuição geográfica.


Subject(s)
Animals , Insect Vectors/classification , Triatominae/classification , Brazil , Chagas Disease/transmission
8.
Mutagenesis ; 25(3): 257-69, 2010 May.
Article in English | MEDLINE | ID: mdl-20123696

ABSTRACT

Diphenyl ditelluride (DPDT) is a potential prototype for the development of novel biologically active molecules. Thus, it is important to evaluate the toxic effects of this compound. In the present study, we evaluated the cytotoxic, genotoxic and mutagenic properties of DPDT in Chinese hamster fibroblast (V79) cells, in strains of the yeast Saccharomyces cerevisiae both proficient and deficient in several DNA repair pathways and in Salmonella typhimurium. DPDT induced frameshift mutations in both S.typhimurium and a haploid wild-type strain of S.cerevisiae. Mutants of S.cerevisiae defective in base excision repair and recombinational repair were more sensitive to DPDT. The results of a lactate dehydrogenase leakage assay suggest that DPDT is cytotoxic to V79 cells. At cytotoxic concentrations, this compound increased thiobarbituric reactive species levels and decreased the glutathione:GSSH ratio in yeast and V79 cells. DPDT generated single- and double-strand DNA breaks in V79 cells, both with and without metabolic activation, as revealed by alkaline and neutral comet assays. Moreover, an induction of oxidative DNA base damage was indicated by a modified comet assay using formamidopyrimidine DNA glycosylase and endonuclease III. Treatment with DPDT also induced micronucleus formation in V79 cells. Pre-incubation with N-acetylcysteine reduced DPDT's oxidative, genotoxic and mutagenic effects in yeast and V79 cells. Our results suggest that the toxic and mutagenic properties of DPDT may stem from its ability to disturb the redox balance of the cell, which leads to oxidative stress and the induction of DNA damage.


Subject(s)
Benzene Derivatives/toxicity , Models, Biological , Mutagens/toxicity , Organometallic Compounds/toxicity , Animals , Benzene Derivatives/chemistry , Biomarkers/metabolism , Cell Death/drug effects , Cell Line , Cell Proliferation/drug effects , Cricetinae , Cricetulus , DNA Damage , L-Lactate Dehydrogenase/metabolism , Microbial Viability/drug effects , Micronuclei, Chromosome-Defective/drug effects , Microsomes/drug effects , Microsomes/metabolism , Mutagenicity Tests , Mutagens/chemistry , Organometallic Compounds/chemistry , Oxidative Stress/drug effects , Point Mutation/genetics , Saccharomyces cerevisiae/cytology , Saccharomyces cerevisiae/drug effects , Salmonella/cytology , Salmonella/drug effects , Thiobarbituric Acid Reactive Substances/metabolism
9.
Mutat Res ; 673(2): 133-40, 2009 Mar 17.
Article in English | MEDLINE | ID: mdl-19429514

ABSTRACT

The trace element selenium (Se), once known only for its potential toxicity, is now a well-established essential micronutrient for mammals. The organoselenium compound diphenyl diselenide (DPDS) has shown interesting antioxidant and neuroprotective activities. On the other hand, this compound has also presented pro-oxidant and mutagenic effects. The compound 3'3-ditrifluoromethyldiphenyl diselenide (DFDD), a structural analog of diphenyl diselenide, has proven antipsychotic activity in mice. Nevertheless, as opposed to DPDS, little is known on the biological and toxicological properties of DFDD. In the present study, we report the genotoxic effects of the organoselenium compound DFDD on Salmonella typhimurium, Saccharomyces cerevisiae and Chinese hamster lung fibroblasts (V79 cells). DFDD protective effects against hydrogen peroxide (H(2)O(2))-induced DNA damage in vitro are demonstrated. DFDD did not cause mutagenic effects on S. typhimurium or S. cerevisiae strains; however, it induced DNA damage in V79 cells at doses higher than 25 microM, as detected by comet assay. DFDD protected S. typhimurium and S. cerevisiae against H(2)O(2)-induced mutagenicity, and, at doses lower than 12.5 microM, prevented H(2)O(2)-induced genotoxicity in V79 cells. The in vitro assays demonstrated that DFDD mimics catalase activity better than DPDS, but neither presents superoxide dismutase action. The products of the reactions of DFDD or DPDS with H(2)O(2) were different, as determined by electrospray mass spectrometry analysis (ESI-MS). These results suggest that DFDD is not mutagenic for bacteria or yeast; however, it may induce weak genotoxic effects on mammalian cells. In addition, DFDD has a protective effect against H(2)O(2)-induced damage probably by mimicking catalase activity, and the distinct products of the reaction DFDD with H(2)O(2) probably have a fundamental role in the protective effects of DFDD.


Subject(s)
Antimutagenic Agents/pharmacology , DNA Damage/drug effects , Organoselenium Compounds/pharmacology , Animals , Catalase/metabolism , Cells, Cultured , Cricetinae , Cricetulus , Cytoprotection/drug effects , Drug Evaluation, Preclinical , Models, Biological , Mutagenicity Tests , Saccharomyces cerevisiae/drug effects , Salmonella typhimurium/drug effects , Stem Cells/drug effects , Superoxide Dismutase/metabolism , Superoxide Dismutase-1
10.
J Photochem Photobiol B ; 96(2): 117-29, 2009 Aug 03.
Article in English | MEDLINE | ID: mdl-19464923

ABSTRACT

The photoprotective effect of the methanolic extracts of three Antarctic plant species - Deschampsia antarctica Desv., Colobanthus quitensis (Kunth) Bartl., and Polytrichum juniperinum Hedw. against UV-induced DNA damage was investigated in hamster lung fibroblasts (V79 cells) and in a biomonitor organism Helix aspersas, using comet assay. The protective, mutagenic, and antimutagenic profiles of these extracts were also evaluated using haploid strains of the simple eukaryote Saccharomyces cerevisiae, and antioxidant activity were investigated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay, as well as the hypoxanthine/xanthine oxidase assay. At the concentration range employed, the extracts were not cytotoxic or mutagenic to S. cerevisiae. In addition, the treatment with these extracts enhanced survival, and decreased induced reverse, frameshift, and forward mutations in a dose-response manner in all UVC doses employed. The plants extracts did not generate DNA strand breaks in V79 cells, and the treatment significantly decreased DNA damage induced by UVC. Extracts significantly decreased UVC-induced lipid peroxidation in V79 cells, showing a clear antioxidant property. Moreover, results of comet assay in V79 cells, employing Fpg, Endo III, and Endo V enzymes, demonstrated significant reduction of UVC-induced DNA damage after pre-incubation with these extracts. The treatment with all tested extracts were much less efficient against UVC-induced cytotoxicity in the yeast strain defective in photolyase as compared to the wild type strain, suggesting that this DNA repair pathway is stimulated by substances present in the extracts. All extracts showed a significant inhibitory effect in the hypoxanthine/xanthine oxidase assay, and they had the ability to scavenge DPPH. In H. aspersas, the treatment was able to protect against UVC-induced damage. In conclusion, D. antarctica, C. quitensis, and P. juniperinum extracts present photoprotective properties, which can be attributed to molecules, such as flavonoids and carotenoids, which act as UV-absorbing molecules and as antioxidants, as well as stimulate DNA-repair processes.


Subject(s)
DNA Damage/drug effects , Models, Biological , Plant Extracts/pharmacology , Ultraviolet Rays , Animals , Antarctic Regions , Cell Line , Cells, Cultured , Cricetinae , DNA Damage/radiation effects , Helix, Snails
11.
Mutat Res ; 652(2): 164-74, 2008 Apr 30.
Article in English | MEDLINE | ID: mdl-18372210

ABSTRACT

The genus Piper belongs to the Piperaceae family, and includes species of commercial and medicinal importance. Chemical studies on Piper species resulted in the isolation of several biologically active molecules, including alkaloid amides, such as piplartine. This molecule, isolated from Piper tuberculatum, has significant cytotoxic activity against tumor cell lines, and presents antifungal, anti-platelet aggregation, anxiolytic, and antidepressant effects. In order to understand the biological properties of piplartine, this study investigated the genotoxicity and the induction of apoptosis by piplartine in V79 cells and its mutagenic and recombinogenic potential in Saccharomyces cerevisiae. Piplartine induced dose-dependent cytotoxicity in S. cerevisiae cultures in either stationary -- or exponential growth phase. In addition, piplartine was not mutagenic when cells were treated during exponential-growth phase and kept in buffer solution, but it increased the frequencies of point, frameshift, and forward mutations when cells were treated in medium during growth. Piplartine treatment induced DNA strand breaks in V79 cells, as detected by neutral and alkaline comet assay. In cell cycle analysis, piplartine induced G2/M cell cycle arrest, probably as a consequence of the DNA damage induced and repair. Moreover, piplartine treatment induced apoptosis in a dose-dependent manner, as observed by a decrease in mitochondrial membrane potential and an increase in internucleosomal DNA fragmentation. These data suggest that the DNA damage caused by piplartine induces G2/M cell cycle arrest, followed by apoptosis. Moreover, we suggest that cells surviving piplartine-induced DNA damage can accumulate mutations, since this alkaloid was mutagenic and recombinogenic in S. cerevisiae assays.


Subject(s)
DNA Damage/drug effects , Mutagenicity Tests/methods , Piper/chemistry , Piperidones/toxicity , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line , Comet Assay , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Membrane Potential, Mitochondrial/drug effects , Saccharomyces cerevisiae/drug effects
12.
Mutagenesis ; 23(2): 93-9, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18267951

ABSTRACT

Ebselen has a wide spectrum of interesting therapeutic actions including antioxidant, cytoprotective, neuroprotective and anti-inflammatory activities. Since its antioxidant effect is very well known, this paper links the effects of ebselen in redox cellular status to its possible involvement in the maintenance of the integrity of genomic information by using Saccharomyces cerevisiae strains proficient and deficient in antioxidant defences and the mammalian V79 cell line. Using the alkaline comet assay, we showed that 5-10 microM ebselen does not induce DNA damage in V79 cells. Similarly, these same concentrations diminished the extent of the DNA damage induced by hydrogen peroxide (H(2)O(2)). The modified comet assay using DNA glycosylases (formamidopyrimidine-DNA glycosylase and endonuclease II) showed that after pre-treatment with ebselen followed by exposure to H(2)O(2), oxidative damage as recognized by these enzymes was significantly lower. In the same way, ebselen showed strong activity against H(2)O(2)-induced oxidative damage in the anti-mutagenic assay using S. cerevisiae N123 strain and in the antioxidative assay by using S. cerevisiae strains lacking antioxidant defences. This antioxidant effect was more pronounced for the gpx3 delta mutant, which indicated that ebselen acts by mimicking the GPx3 catalytic activity. The results confirm that ebselen is involved in antioxidant defence and that its antioxidant ability contributes to its anti-mutagenic and anti-genotoxic action.


Subject(s)
Antimutagenic Agents/pharmacology , Antioxidants/pharmacology , Azoles/pharmacology , Organoselenium Compounds/pharmacology , Saccharomyces cerevisiae/drug effects , Animals , Antimutagenic Agents/chemistry , Antioxidants/chemistry , Azoles/chemistry , Cell Line , Comet Assay , Cricetinae , DNA Damage/drug effects , Gene Deletion , Glutathione Peroxidase/genetics , Hydrogen Peroxide/toxicity , Isoindoles , Organoselenium Compounds/chemistry , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics
13.
Toxicol In Vitro ; 21(8): 1442-52, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17683899

ABSTRACT

Plants of the genus Hibiscus thrives produce a diversity of molecules with bioactive properties. In a previous study of Hibiscus tiliaceus L. methanolic extract (HME) using bacteria and yeast, as test media, it has been shown that HME strongly inhibited the mutagenic action of H(2)O(2) or tert-butyl-hydroperoxide (t-BHP). Here, our interest is to evaluate the genotoxicity and the antigenotoxic/antimutagenic properties of HME using oxidative challenge with H(2)O(2) and t-BHP in V79 cells. We determined cytotoxicity using clonal survival assay; evaluated DNA damage using the comet assay and the micronucleus test in binucleated cells besides of the lipid peroxidation degree and the reduced glutathione content. We examined the ability of HME in quenching hydroxyl radical by means of a HPLC-based method utilizing the hypoxanthine/xanthine oxidase assay. At concentrations ranging from 0.001 to 0.1mg/mL, HME was not cytotoxic, genotoxic or mutagenic. Treatment with non-cytotoxic concentrations of HME increased cell survival after H(2)O(2) and t-BHP exposure and prevented DNA damage. The pre-treatment with HME also was able to decrease the mutagenic effect of these genotoxins, evaluated using the micronucleus test. HME prevented the increase in lipid peroxidation and decrease in GSH content in response to the oxidative challenge. Therefore, the ability in preventing against H(2)O(2)- and t-BHP-induced GSH depletion and lipid peroxidation was probably a major contribution to the cytoprotective effects. Moreover, HME acts as a hydroxyl radical scavenger. In summary, HME did not have a harmful or inhibitory effect on the growth of V79 cells and presented antioxidant activity, consequently, both antigenotoxic and antimutagenic effects against oxidative DNA damage.


Subject(s)
Hibiscus/chemistry , Hydrogen Peroxide/toxicity , Mutagens/toxicity , Plant Extracts/pharmacology , tert-Butylhydroperoxide/toxicity , Animals , Cell Line , Chromosomes/drug effects , Cricetinae , Cytotoxins/toxicity , DNA Damage , Dose-Response Relationship, Drug , Free Radical Scavengers , Glutathione , Hydroxyl Radical , Lipid Peroxidation , Plant Extracts/chemistry
14.
Mutat Res ; 633(1): 35-45, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17590383

ABSTRACT

Diphenyl diselenide (DPDS) is an organoselenium compound with interesting pharmacological activities and various toxic effects. In previous reports, we demonstrated the pro-oxidant action and the mutagenic properties of this molecule in bacteria, yeast and cultured mammalian cells. This study investigated the genotoxic effects of DPDS in multiple organs (brain, kidney, liver, spleen, testes and urinary bladder) and tissues (bone marrow, lymphocytes) of mice using in vivo comet assay, in order to determine the threshold of dose at which it has beneficial or toxic effects. We assessed the mechanism underlying the genotoxicity through the measurement of GSH content and thiobarbituric acid reactive species, two oxidative stress biomarkers. Male CF-1 mice were given 0.2-200 micromol/kg BW DPDS intraperitonially. DPDS induced DNA damage in brain, liver, kidney and testes in a dose response manner, in a broad dose range at 75-200 micromol/kg with the brain showing the highest level of damage. Overall, our analysis demonstrated a high correlation among decreased levels of GSH content and an increase in lipid peroxidation and DNA damage. This finding establishes an interrelationship between pro-oxidant and genotoxic effects. In addition, DPDS was not genotoxic and did not increase lipid peroxidation levels in any organs at doses < 50 micromol/kg. Finally, pre-treatment with N-acetyl-cysteine completely prevented DPDS-induced oxidative damage by the maintenance of cellular GSH levels, reinforcing the positive relationship of DPDS-induced GSH depletion and DNA damage. In summary, DPDS induces systemic genotoxicity in mammals as it causes DNA damage in vital organs like brain, liver, kidney and testes.


Subject(s)
Benzene Derivatives/toxicity , DNA Damage/drug effects , Lymphocytes/drug effects , Organoselenium Compounds/toxicity , Oxidants/toxicity , Acetylcysteine/therapeutic use , Animals , Cell Survival/drug effects , Cells, Cultured/drug effects , Comet Assay , Dose-Response Relationship, Drug , Free Radical Scavengers/therapeutic use , Glutathione/metabolism , Lipid Peroxidation/drug effects , Male , Mice , Mutagenicity Tests , Organ Culture Techniques , Tissue Distribution
15.
Mutat Res ; 631(1): 44-54, 2007 Jul 10.
Article in English | MEDLINE | ID: mdl-17507284

ABSTRACT

Diphenyl diselenide (DPDS) is an electrophilic reagent used in the synthesis of a variety of pharmacologically active organic selenium compounds. Studies have shown its antioxidant, hepatoprotective, neuroprotective, anti-inflammatory, and antinociceptive effects. We recently showed the antioxidant effect of DPDS in V79 cells, and established the beneficial and toxic doses of this compound in this cell line. Here, we report the antigenotoxic and antimutagenic properties of DPDS, investigated by using a permanent lung fibroblast cell line derived from Chinese hamsters. We determined the cytotoxicity by clonal survival assay, and evaluated DNA damage in response to several mutagens by comet assay and micronucleus test in binucleated cells. In the clonal survival assay, at concentrations ranging from 1.62 to 12.5microM, DPDS was not cytotoxic, while at concentrations up to 25microM, it significantly decreased survival. The treatment with this organoselenium compound at non-cytotoxic dose range increased cell survival after challenge with hydrogen peroxide, methyl-methanesulphonate, and UVC radiation, but did not protect against 8-methoxypsoralen plus UVA-induced cytotoxicity. In addition, the treatment prevented induced DNA damage, as verified in the comet assay. The mutagenic effect of these genotoxins, as measured by the micronucleus test, similarly attenuated or prevented cytotoxicity and DNA damage. Treatment with DPDS also decreased lipid peroxidation levels after exposure to hydrogen peroxide MMS, and UVC radiation, and increased glutathione peroxidase activity in the extracts. Our results clearly demonstrate that DPDS at low concentrations presents antimutagenic properties, which are most probably due to its antioxidant properties.


Subject(s)
Antimutagenic Agents/pharmacology , Antioxidants/pharmacology , Benzene Derivatives/pharmacology , Mutagens/toxicity , Organoselenium Compounds/pharmacology , Animals , Catalase/metabolism , Cell Line , Cell Survival/drug effects , Comet Assay , Cricetinae , Cricetulus , DNA Damage , Glutathione Peroxidase/metabolism , Hydrogen Peroxide/toxicity , Lipid Peroxidation/drug effects , Methyl Methanesulfonate/toxicity , Micronucleus Tests , Mutagenicity Tests , PUVA Therapy/adverse effects , Superoxide Dismutase/metabolism , Ultraviolet Rays/adverse effects
16.
Mutat Res ; 628(2): 87-98, 2007 Apr 02.
Article in English | MEDLINE | ID: mdl-17223377

ABSTRACT

Diphenyl diselenide (DPDS) is an electrophilic reagent used in the synthesis of a variety of pharmacologically active organic selenium compounds, and may increase the risk of human exposure to this chemical at the workplace. In a previous study, we demonstrated the pro-oxidant action and the mutagenic properties of this compound on bacteria and yeast. In the present study, we evaluated the putative cytotoxic, pro-oxidant, genotoxic, and mutagenic properties of this molecule in V79 Chinese lung fibroblast cells. When cells were treated with increasing concentrations of DPDS, its cytotoxic activity, as determined using four cell viability endpoints, occurs in doses up to 50 microM. The MTT reduction was stimulated, which may indicate reactive oxygen species (ROS) generation. Accordingly, the treatment of cells for 3h with cytotoxic doses of DPDS increased TBARS levels, and sensitized cells to oxidative challenge, indicating a pro-oxidant effect. The measurement of total, reduced, and oxidized glutathione showed that DPDS can lead to lower intracellular glutathione depletion, with no increase in the oxidation rate in a dose- and time-dependent manner. At the higher doses, DPDS generates DNA strand breaks, as observed using the comet assay. The treatment also induced an increase in the number of binucleated cells in the micronucleus test, showing mutagenic risk by this molecule at high concentrations. Finally, pre-incubation with N-acetylcysteine, which restored GSH to normal levels, annulled DPDS pro-oxidant and genotoxic effects. These findings show that DPDS-induced oxidative stress and toxicity are closely related to intracellular level of reduced glutathione. Moreover, at lower doses, this molecule has antioxidant properties, protecting the cell against oxidative damage induced by hydrogen peroxide.


Subject(s)
Benzene Derivatives/toxicity , Fibroblasts/drug effects , Lung/drug effects , Mutagenicity Tests/methods , Organoselenium Compounds/toxicity , Animals , Cell Survival/drug effects , Cells, Cultured , Cricetinae , Cricetulus , DNA Damage , Dose-Response Relationship, Drug , Lipid Peroxidation/drug effects , Sulfhydryl Compounds/metabolism
17.
J Agric Food Chem ; 54(19): 7324-30, 2006 Sep 20.
Article in English | MEDLINE | ID: mdl-16968101

ABSTRACT

The genus Hibiscus thrives in a variety of climates and produces a diversity of natural compounds with bioactive properties. We have studied the chemical composition and the in vivo antioxidant properties of Hibiscus tiliaceus L. methanolic flower extract, as well as its mutagenic/antimutagenic effects. Vitamin E and some stigmasterol derivatives that might confer an antioxidant effect to the extract were present. Treatment with this extract protected several Saccharomyces cerevisiae strains defective in antioxidant defenses against H2O2 and t-BOOH cytotoxicities, showing a clear antioxidant activity. The effect is the same for all strains used, independent of the antioxidant defense disrupted, suggesting that protection may be due to molecules that act as versatile and wide spectrum nonenzymatic antioxidants, such as vitamins or phytosterols. The extract was not mutagenic in either Salmonella typhimurium or S. cerevisiae and showed a significant antimutagenic action against oxidative mutagens in S. cerevisiae.


Subject(s)
Antimutagenic Agents/pharmacology , Antioxidants/pharmacology , Flowers/chemistry , Hibiscus/chemistry , Plant Extracts/pharmacology , Methanol , Mutagenicity Tests
18.
Mutat Res ; 563(2): 107-15, 2004 Oct 10.
Article in English | MEDLINE | ID: mdl-15364277

ABSTRACT

Diphenyl diselenide (DPDS) is an electrophilic reagent used in the synthesis of a variety of pharmacologically active organic selenium compounds. This may increase the risk of human exposure to the chemical at the workplace. We have determined its mutagenic potential in the Salmonella/microsome assay and used the yeast Saccharomyces cerevisiae to assay for putative genotoxicity, recombinogenicity and to determine whether DNA damage produced by DPDS is repairable. Only in exponentially growing cultures was DPDS able to induce frameshift mutations in S. typhimurium and haploid yeast and to increase crossing over and gene conversion frequencies in diploid strains of S. cerevisiae. Thus, DPDS presents a behavior similar to that of an intercalating agent. Mutants defective in excision-resynthesis repair (rad3, rad1), in error-prone repair (rad6) and in recombinational repair (rad52) showed higher than WT-sensitivity to DPDS. It appears that this compound is capable of inducing single and/or double strand breaks in DNA. An epistatic interaction was shown between rad3-e5 and rad52-1 mutant alleles, indicating that excision-resynthesis and strand-break repair may possess common steps in the repair of DNA damage induced by DPDS. DPDS was able to enhance the mutagenesis induced by oxidative mutagens in bacteria. N-acetylcysteine, a glutathione biosynthesis precursor, prevented mutagenesis induced by DPDS in yeast. We have shown that DPDS is a weak mutagen which probably generates DNA strand breaks through both its intercalating action and pro-oxidant effect.


Subject(s)
Bacteria/drug effects , Benzene Derivatives/toxicity , Organoselenium Compounds/toxicity , Saccharomyces cerevisiae/drug effects , Bacteria/genetics , DNA Repair , DNA, Mitochondrial/drug effects , Mutagenicity Tests , Recombination, Genetic , Saccharomyces cerevisiae/genetics
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