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1.
Food Chem Toxicol ; 155: 112357, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34217737

RESUMO

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, the sixth in the series, will summarize the re-evaluation of eight NFCs whose constituent profiles are characterized by significant amounts of eucalyptol and/or other cyclic ethers. This re-evaluation was based on a procedure first published in 2005 and subsequently updated in 2018 that evaluates the safety of naturally occurring mixtures for their intended use as flavoring ingredients. The procedure relies on a complete chemical characterization of the NFC intended for commerce and the organization of its chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of the constituents of the congeneric groups and the NFC under evaluation. Eight NFCs derived from the Eucalyptus, Melaleuca, Origanum, Laurus, Rosmarinus and Salvia genera were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.


Assuntos
Éteres Cíclicos/toxicidade , Aromatizantes/toxicidade , Óleos de Plantas/toxicidade , Animais , Células CHO , Linhagem Celular Tumoral , Qualidade de Produtos para o Consumidor , Cricetulus , Éteres Cíclicos/química , Eucaliptol/toxicidade , Feminino , Aromatizantes/química , Humanos , Masculino , Camundongos , Testes de Mutagenicidade , Nível de Efeito Adverso não Observado , Óleos de Plantas/química , Plantas/química , Gravidez , Ratos Wistar , Medição de Risco , Salmonella typhimurium/efeitos dos fármacos
2.
Toxins (Basel) ; 13(2)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499131

RESUMO

Two different types of polycyclic ether toxins, namely brevisulcenals (KBTs) and brevisulcatic acids (BSXs), produced by the red tide dinoflagellate Karenia brevisulcata, were the cause of a toxic incident that occurred in New Zealand in 1998. Four major components, KBT-F, -G, -H, and -I, shown to be cytotoxic and lethal in mice, were isolated from cultured K. brevisulcata cells, and their structures were elucidated by spectroscopic analyses. New analogues, brevisulcenal-A1 (KBT-A1) and brevisulcenal-A2 (KBT-A2), toxins of higher polarity than that of known KBTs, were isolated from neutral lipophilic extracts of bulk dinoflagellate culture extracts. The structures of KBT-A1 and KBT-A2 were elucidated as sulfated analogues of KBT-F and KBT-G, respectively, by NMR and matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI TOF/TOF), and by comparison with the spectra of KBT-F and KBT-G. The cytotoxicities of the sulfate analogues were lower than those of KBT-F and KBT-G.


Assuntos
Dinoflagellida/metabolismo , Éteres Cíclicos/isolamento & purificação , Sulfatos/isolamento & purificação , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Éteres Cíclicos/toxicidade , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-Atividade , Sulfatos/toxicidade
3.
Fitoterapia ; 142: 104520, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32088280

RESUMO

Chemical and biocatalytic synthesis of seven previously undescribed marchantin A ester derivatives has been presented. Chemical synthesis afforded three peresterified bisbibenzyl products (TE1-TE3), while enzymatic method, using lipase, produced regioselective monoester derivatives (ME1-ME4). The antiproliferative activities of all prepared derivatives of marchantin A were tested on MRC-5 healthy human lung fibroblast, A549 human lung cancer, and MDA-MB-231 human breast cancer cell lines. All tested esters were less cytotoxic in comparison to marchantin A, but they also exhibited lower cytotoxicity against healthy cells. Monoesters displayed higher cytotoxic activities than the corresponding peresterified products, presumably due to the presence of free catechol group. Monohexanoyl ester ME3 displayed the same IC50 like marchantin A against MDA-MB-231 cells, but the selectivity was higher. In this way, regioselective enzymatic monoesterification enhanced selectivity of marchantin A. ME3 was also the most active among all derivatives against lung cancer cells A549 with the slightly lower activity and selectivity in comparison to marchantin A.


Assuntos
Antineoplásicos Fitogênicos/química , Bibenzilas/química , Éteres Cíclicos/química , Células A549 , Antineoplásicos Fitogênicos/toxicidade , Bibenzilas/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Esterificação , Éteres Cíclicos/toxicidade , Humanos
4.
Food Chem Toxicol ; 97S: S192-S200, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27697541

RESUMO

: The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic nor does it have skin sensitization potential. The local respiratory toxicity endpoint was completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (1.4 mg/day). The repeated dose toxicity endpoint was completed using ethylene dodecanedioate (CAS # 54982-83-1) as a suitable read across analog, which provided a MOE > 100. The developmental and reproductive toxicity endpoint was completed using oxacyclohexadec-12-en-2-one, (12E)- (CAS # 111879-80-2) as a suitable read across analog, which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra along with data on the target material. The environmental endpoint was completed as described in the RIFM Framework along with data on the suitable read across analog oxacyclohexadec-12-en-2-one, (12E)- (CAS # 111879-80-2).


Assuntos
Éteres Cíclicos/toxicidade , Perfumes/toxicidade , Testes de Toxicidade/métodos , Animais , Qualidade de Produtos para o Consumidor , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Determinação de Ponto Final , Éteres Cíclicos/química , Nível de Efeito Adverso não Observado , Perfumes/química , Ratos , Medição de Risco
5.
Chem Res Toxicol ; 25(10): 2092-102, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22889134

RESUMO

Organic electrophiles have the potential to covalently attack DNA bases, and thus initiate mutagenic and carcinogenic processes. In this context, aromatic nitrogen sites of the DNA bases are often particularly nucleophilic, with guanine N7 being one of the most favored sites of adduct formation with electrophilic xenobiotics. Employing 4-(4-nitrobenzyl)pyridine (NBP) as model nucleophile with a respective aromatic ═N- unit, a new kinetic variant of a photometric chemoassay for sensing the DNA reactivity of organic compounds is introduced and applied to 21 three- and four-membered oxygen and sulfur heterocycles (15 epoxides, two thiiranes, three oxetanes, and one thietane). Besides six unreactive compounds (oxetanes, thietane, and aliphatic epoxides with six or more side-chain carbons), second-order rate constants of the electrophile-NBP reaction, k(NBP), were obtained for 15 compounds, ranging from (1.16 ± 0.05)·10⁻³ to (36.5 ± 0.6)·10⁻³ L mol⁻¹ min⁻¹ in a methanol/tris-HCl buffer (16/84 v/v) reaction medium. Solvolysis as confounding factor was addressed by determining respective first-order rate constants k(solv). Analysis of the k(NBP) values resulted in structure-reactivity relationships, and comparison with literature data from the Ames test bacterial strains TA100, TA1535, and TA97 (Salmonella typhimurium) as well as from WP2 uvrA (Escherichia coli) revealed significant log-log relationships between the mutagenic potency of the heterocycles and their reactivity toward NBP. The latter demonstrates the potential of the NBP chemoassay as a nonanimal component of integrated testing strategies for REACH, enabling an efficient screening of organic electrophiles with respect to their DNA reactivity and associated mutagenicity and carcinogenicity.


Assuntos
Compostos de Epóxi/toxicidade , Éteres Cíclicos/toxicidade , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Piridinas/química , Compostos de Enxofre/toxicidade , Compostos de Epóxi/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Éteres Cíclicos/química , Mutagênicos/química , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Compostos de Enxofre/química
6.
J Am Chem Soc ; 134(10): 4963-8, 2012 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-22372917

RESUMO

A novel marine toxin, brevisulcenal-F (KBT-F, from karenia brevisulcata toxin) was isolated from the dinoflagellate Karenia brevisulcata. A red tide of K. brevisulcata in Wellington Harbour, New Zealand, in 1998 was extremely toxic to fish and marine invertebrates and also caused respiratory distress in harbor bystanders. An extract of K. brevisulcata showed potent mouse lethality and cytotoxicity, and laboratory cultures of K. brevisulcata produced a range of novel lipid-soluble toxins. A lipid soluble toxin, KBT-F, was isolated from bulk cultures by using various column chromatographies. Chemical investigations showed that KBT-F has the molecular formula C(107)H(160)O(38) and a complex polycyclic ether nature. NMR and MS/MS analyses revealed the complete structure for KBT-F, which is characterized by a ladder-frame polyether scaffold, a 2-methylbut-2-enal terminus, and an unusual substituted dihydrofuran at the other terminus. The main section of the molecule has 17 contiguous 6- and 7-membered ether rings. The LD(50) (mouse i.p.) for KBT-F was 0.032 mg/kg.


Assuntos
Éteres Cíclicos/toxicidade , Peixes , Proliferação Nociva de Algas , Animais , Éteres Cíclicos/química , Éteres Cíclicos/isolamento & purificação , Camundongos , Nova Zelândia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrofotometria Ultravioleta
9.
Food Chem Toxicol ; 49 Suppl 2: S174-82, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21801781

RESUMO

A toxicologic and dermatologic review of ethylene brassylate when used as a fragrance ingredient is presented. Ethylene brassylate is a member of the fragrance structural group macrocyclic lactone and lactide derivatives. The fragrance ingredient described herein is one of 12 structurally diverse C14, C15, and C16 compounds that include (7) saturated mono-and (2) saturated di-ester lactones and (3) unsaturated lactones. For the latter, the double bond is not adjacent to (in conjugation with) the ester group. This review contains a detailed summary of all available toxicology and dermatology papers that are related to ethylene brassylate and is not intended as a stand-alone document. Available data were evaluated, then summarized, and includes: physical properties; acute toxicity; skin irritation; skin sensitization; elicitation; phototoxicity; repeated dose; and genotoxicity data. A safety assessment of the entire macrocyclic lactone and lactide derivatives will be published simultaneously with this document. Please refer to Belsito et al. (2011) for an overall assessment of the safe use of this material and all macrocyclic lactone and lactide derivatives in fragrances. Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Hanifin, J.H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2011. A toxicologic and dermatologic assessment of macrocylic lactone and lactide derivatives when used as fragrance ingredients.


Assuntos
Éteres Cíclicos/química , Éteres Cíclicos/toxicidade , Perfumes/química , Perfumes/toxicidade , Animais , Dano ao DNA/efeitos dos fármacos , Dermatite Alérgica de Contato/patologia , Dermatite Fototóxica/patologia , Traumatismos Oculares/induzido quimicamente , Traumatismos Oculares/patologia , Humanos , Mucosa/efeitos dos fármacos , Mucosa/patologia , Odorantes , Pele/efeitos dos fármacos , Pele/patologia , Testes de Toxicidade/métodos
10.
Bioorg Med Chem ; 18(18): 6725-33, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20724170

RESUMO

P-glycoprotein (P-gp) is known to mediate multidrug resistance (MDR) by acting as an efflux pump to actively transport chemotherapeutic agents out of carcinoma cells. Inhibition of P-gp function may represent one of the strategies to reverse MDR. We have previously reported that marchantin C (MC), a macrocyclic bisbibenzyl compound from liverworts, exerts anti-tumor activity as an antimitotic agent. This study was designed to evaluate the possible modulatory effect of MC and its three synthetic derivatives (MC1, MC2 and MC3) on P-gp in VCR-resistant KB/VCR cells. Results of the cytotoxicity assay revealed that MC was the most potent inhibitor of cell proliferation in both KB and KB/VCR cells among these four compounds, while the three MC-derived chemicals had little anti-proliferative activity under the same condition. However, in P-gp-expressing MDR cells, analysis of potency of these compounds in enhancing cytotoxicity of VCR led to the identification of MC2 as a more effective chemical on reversal of resistance. Further study showed that MC2 was able to reduce efflux of rhodamine-123, and in turn, increase the accumulation of rhodamine-123 and adriamycin in KB/VCR cells, indicating that MC2 re-sensitized cells to VCR by inhibition of the P-gp transport activity. In addition, the combination of MC2 and VCR at a concentration that does not inhibit cell growth resulted in an induction of apoptosis in KB/VCR cells. These results suggest that MC2, as a novel and effective inhibitor of P-gp, may find potential application as an adjunctive agent with conventional chemotherapeutic drugs to reverse MDR in P-gp overexpressing cancer cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/toxicidade , Bibenzilas/química , Catecóis/química , Éteres Cíclicos/química , Éteres Fenílicos/química , Estilbenos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Bibenzilas/síntese química , Bibenzilas/toxicidade , Catecóis/síntese química , Catecóis/toxicidade , Linhagem Celular Tumoral , Doxorrubicina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Éteres Cíclicos/síntese química , Éteres Cíclicos/toxicidade , Humanos , Éteres Fenílicos/síntese química , Éteres Fenílicos/toxicidade , Rodamina 123/metabolismo , Estilbenos/síntese química , Estilbenos/toxicidade , Vincristina/farmacologia
11.
Chem Res Toxicol ; 23(7): 1275-81, 2010 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-20550097

RESUMO

Small, highly strained heterocycles are archetypical alkylating agents (oxiranes, beta-lactones, aziridinium, and thiirinium ions). Oxetanes, which are tetragonal ethers, are higher homologues of oxiranes and reduced counterparts of beta-lactones, and would therefore be expected to be active alkylating agents. Oxetanes are widely used in the manufacture of polymers, especially in organic light-emitting diodes (OLEDs), and are present, as a substructure, in compounds such as the widely used antimitotic taxol. Whereas the results of animal tests suggest that trimethylene oxide (TMO), the parent compound, and beta,beta-dimethyloxetane (DMOX) are active carcinogens at the site of injection, no studies have explored the alkylating ability and genotoxicity of oxetanes. This work addresses the issue using a mixed methodology: a kinetic study of the alkylation reaction of 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilicity similar to that of DNA bases, by three oxetanes (TMO, DMOX, and methyloxetanemethanol), and a mutagenicity, genotoxicity, and cell viability study (Salmonella microsome test, BTC E. coli test, alkaline comet assay, and MTT assay). The results suggest either that oxetanes lack genotoxic capacity or that their mode of action is very different from that of epoxides and beta-lactones.


Assuntos
Alquilantes/química , Éteres Cíclicos/química , Alquilantes/toxicidade , Alquilação , Carcinógenos/química , Carcinógenos/toxicidade , Ensaio Cometa , Éteres Cíclicos/toxicidade , Óxido de Etileno/química , Cinética , Lactonas/química
12.
Toxicol Sci ; 95(2): 427-35, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17118960

RESUMO

Azaspiracids cause severe damages in the epithelium of several organs. In this study we have investigated the effects of azaspiracid-1 (AZA-1) on two epithelial cell lines. Nanomolar concentrations of AZA-1 reduced MCF-7 cell proliferation and impaired cell-cell adhesion. AZA-1 altered the cellular pool of the adhesion molecule E-cadherin by inducing a dose- and time-dependent accumulation of an E-cadherin fragment (E-cadherin-related antigen [ECRA(100)]), with a concentration inducing the half-maximal effect (EC(50)) of 0.47nM. The immunological characterization of ECRA(100) revealed that it consists of an E-cadherin molecule lacking the intracellular domain, and these data showed that the effect induced by AZA-1 in MCF-7 cells is undistinguishable from that induced by yessotoxin (YTX) in the same experimental system. A comparison of toxin effects in MCF-7 and Caco 2 cells confirmed that the effects induced by AZA-1 and YTX are undistinguishable in these cells. Treatment of fibroblasts with AZA-1 did not affect the cellular pool of N-cadherin showing that the toxin effect is cadherin-specific. A comparison of the effects induced by AZA-1, YTX, and okadaic acid on F-actin and E-cadherin in MCF-7 and Caco 2 cells showed that 1nM AZA-1 did not cause significant changes in F-actin and that accumulation of ECRA(100) did not correlate with decreased levels of F-actin under our experimental conditions. Matching our results with those available in literature, we notice that, when molecular effects induced by AZA-1 and YTX have been studied in the same in vitro systems, experimental data show that they are undistinguishable in terms of sensitive cellular parameters, effective doses, and kinetics of responses in several cell lines. The possibility that azaspiracids and YTXs might share their molecular mechanism(s) of action in defined biological settings should be considered.


Assuntos
Caderinas/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Toxinas Marinhas/toxicidade , Compostos de Espiro/toxicidade , Actinas/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Éteres Cíclicos/toxicidade , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Toxinas Marinhas/isolamento & purificação , Camundongos , Venenos de Moluscos , Mytilus edulis/química , Oxocinas/toxicidade , Compostos de Espiro/isolamento & purificação , Fatores de Tempo
13.
Toxicology ; 227(1-2): 145-55, 2006 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-16950554

RESUMO

YTX has been shown to disrupt the E-cadherin-catenin system in cultured epithelial cells, raising some concern that ingestion of seafood contaminated by YTX might favour tumour spreading and metastasis formation in vivo. In order to probe whether YTX might affect cadherin systems in vivo, we have set up a study involving repeated oral dosing of the toxin in mice (1mg/kg/day, for 7 days) and analysis of E-cadherin and N-cadherin in tissue extracts obtained at the end of the dosing scheme, as well as 1 and 3 months after YTX administration. We found that the E-cadherin pools obtained from lung and kidney were not altered by YTX in any of our experimental conditions. Extracts from mouse colon contained intact E-cadherin and an E-cadherin fragment of about 90 kDa (ECRA(90)), displaying a molecular alteration resembling that caused by YTX in cultured cells. We found that the relative proportion of ECRA(90), as compared to intact E-cadherin, was higher in colon extracts from control mice than from YTX-treated animals, indicating that oral administration of YTX to mice stabilizes E-cadherin of mouse colon. No significant difference could be detected in samples prepared from colons obtained 30 or 90 days after termination of YTX treatment. Oral administration of YTX to mice did not lead to a significant increase in the fragments of E-cadherin detectable in serum, neither it altered the N-cadherin pool of mouse heart. Electron microscopy analysis showed no substantial ultrastructural differences between controls and YTX-treated mice. Our findings show that ingestion of food contaminated by YTX poses a low risk of disruption of the E-cadherin system in vivo.


Assuntos
Caderinas/metabolismo , Colo/efeitos dos fármacos , Éteres Cíclicos/toxicidade , Oxocinas/toxicidade , Administração Oral , Animais , Linhagem Celular , Colo/metabolismo , Colo/ultraestrutura , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Feminino , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/ultraestrutura , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/ultraestrutura , Camundongos , Microscopia Eletrônica de Transmissão , Venenos de Moluscos , Miocárdio/metabolismo , Miocárdio/ultraestrutura
14.
Eur J Histochem ; 49(2): 179-88, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15967746

RESUMO

The toxicity of okadaic acid (OA) and yessotoxins (YTXs) was studied in mice orally fed on (i) OA (17.80+/-2.41 microg/kg) for 24 h and mouse feed for 24 h; (ii) OA (17.2+/-2.13 microg/kg) plus YTXs (1.30+/-0.12 mg/kg) for 24 h and mouse feed for 24 h; (iii) OA (18.88+/-1.86 microg/kg) plus YTXs (1.45+/-0.12 mg/kg) for 24 h. After toxin treatments the thymus and spleen were examined. More severe morpho-functional modifications were found in the thymus, which presented atrophy, a significant depletion in the lymphoid compartment and angiogenesis. In spite of the impairment, a number of inflammatory cells, reactive to anti-cytokine antibodies, were recruited. Moreover, greater expression of matrix metalloproteinase-9, particularly in cells located near new blood vessels, was observed. Thymus injury was still observed after 48 h. Histopathological changes to the spleen were more evident in mice orally treated for 24 h and immediately sacrificed. The organ showed a significant loss of volume and a fibrous component invaded regions involved in immune functions. In white pulp the marginal zones were reduced, lymphoid nodules contained large germinal centres and the periarteriolar lymphoid sheaths showed cellular depletion. An inflammatory cell response was activated by the recruitment of granulocytes, an increased number of active macrophages and increased immunoreactivity to cytokines. Unlike in the thymus, some evidence of recovery was seen in the spleen. The data suggest that low oral doses of OA alone or OA plus YTXs are able to provoke immunostimulation and systemic immunotoxicity, thus also indicative of tumorigenic properties.


Assuntos
Bivalves/química , Éteres Cíclicos/toxicidade , Contaminação de Alimentos , Ácido Okadáico/toxicidade , Oxocinas/toxicidade , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos , Ração Animal , Animais , Masculino , Camundongos , Venenos de Moluscos , Baço/patologia , Timo/patologia
15.
Chem Res Toxicol ; 17(9): 1251-7, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15377159

RESUMO

The structure-activity relationship of yessotoxins (YTX) has been probed by measuring the potency of several YTX analogues to cause the accumulation of a 100 kDa MW fragment of E-cadherin in MCF-7 breast cancer cells. Under our experimental conditions, the EC(50) of YTX, the reference compound, was 0.55 nM. The introduction of a methylene unit adjacent to one of the sulfate groups, as is the case with the homoyessotoxin molecule, did not appear to greatly affect the potency of the analogue, as the measured EC(50) for this compound was 0.62 nM. The EC(50) values we measured for 45-hydroxyhomoyessotoxin and carboxyyessotoxin were about 9.4 and 26 nM, respectively, whereas the EC(50) of noroxoyessotoxin, lacking most of the C(9) chain, was about 50 nM. Thus, significant differences in the potencies of YTX analogues were found when structural changes involved the C(9) terminal chain of these compounds, leading to the conclusion that this portion of the molecule is essential for the activity of YTX in MCF-7 cells. A comparison of our findings with available information regarding the potency of YTX and its analogues in other experimental systems shows that the EC(50)'s we measured for the different compounds are up to 200-fold lower and vary in a wider concentration range. We speculate that YTX effects could involve two separate receptorial systems.


Assuntos
Células Epiteliais/efeitos dos fármacos , Éteres Cíclicos/química , Éteres Cíclicos/toxicidade , Venenos de Moluscos/química , Venenos de Moluscos/toxicidade , Oxocinas/química , Oxocinas/toxicidade , Animais , Células Cultivadas , Relação Estrutura-Atividade , Testes de Toxicidade
16.
Toxicon ; 44(1): 83-90, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15225566

RESUMO

Histological and immunocytochemical investigations were performed on different organs (brain, duodenum and thymus) of mice following lethal (420 microg/kg) or sublethal (10 microg/kg) intraperitoneal injection of yessotoxin (YTX). No morpho-functional modifications were observed in large neurons of the cerebral and cerebellar cortex with the sub-lethal dose, nor in the cerebral cortex with the lethal dose. The duodenum also did not show significant alterations. However, there was an inflammation response to the toxin, in which blood cells and cytokines were involved. This was more evident with the lethal YTX dose. The thymus and, in general, the immune system are the main targets of YTX at both the concentrations used. Furthermore, the alterations present in the thymus may support tumorigenic implications.


Assuntos
Éteres Cíclicos/toxicidade , Sistema Imunitário/efeitos dos fármacos , Oxocinas/toxicidade , Timo/efeitos dos fármacos , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Duodeno/efeitos dos fármacos , Éteres Cíclicos/administração & dosagem , Histocitoquímica , Imuno-Histoquímica , Injeções Intraperitoneais , Camundongos , Venenos de Moluscos , Oxocinas/administração & dosagem
17.
Biochim Biophys Acta ; 1656(2-3): 139-47, 2004 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-15178475

RESUMO

The diarrhetic poisoning by bivalve molluscs, diarrhetic shellfish poisoning, is due to consumption of mussels containing biotoxins produced by some Dinoflagellate species. Toxic effects of yessotoxin (YTX) include morphological alterations of mitochondria from heart and liver but the biochemical basis for these alterations is completely unknown. This paper demonstrates that YTX is a very powerful compound that opens the permeability transition pore (PTP) of the inner mitochondrial membrane of rat liver mitochondria at nanomolar concentrations. The effect requires the presence of a permissive level of calcium, by itself incapable of opening the pore. The direct effect of YTX on PTP is further confirmed by the inhibition exerted by cyclosporin A (CsA) that is known as a powerful inhibitor of PTP opening. Moreover, YTX induces membrane depolarization as shown by the quenching of tetramethylrhodamine methyl ester (TMRM), also prevented by the addition of CsA. YTX caused PTP opening in Morris Hepatoma 1C1 cells, as shown by the occurrence of CsA-sensitive depolarization within minutes of the addition of submicromolar concentrations of the toxin. These results provide a biochemical basis for the mitochondrial alterations observed in the course of intoxication with YTX, offering the first clue into the pathogenesis of diseases caused by YTX, and providing a novel tool to study the PTP in situ.


Assuntos
Bivalves/química , Éteres Cíclicos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Venenos de Moluscos/metabolismo , Oxocinas/metabolismo , Permeabilidade/efeitos dos fármacos , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Ciclosporina/farmacologia , Inibidores Enzimáticos/farmacologia , Éteres Cíclicos/química , Éteres Cíclicos/toxicidade , Corantes Fluorescentes/metabolismo , Membranas Intracelulares , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Estrutura Molecular , Venenos de Moluscos/química , Venenos de Moluscos/toxicidade , Oxocinas/química , Oxocinas/toxicidade , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Rodaminas/metabolismo , Fatores de Tempo
18.
Environ Health ; 2: 3, 2003 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-12685935

RESUMO

BACKGROUND: Metal-working fluids contain complex mixtures of chemicals and metal workers constitute a potential risk group for the development of allergic contact dermatitis. CASE PRESENTATION: Two metal workers developed allergic contact dermatitis on the hands and lower arms from exposure to a neat oil used in metal processing. Patch testing revealed that the relevant contact allergen was a cycloaliphatic epoxy resin, 1,2-cyclohexanedicarboxylic acid, bis(oxiranylmethyl) ester, added to the oil as a stabilizer. None of the patients had positive reactions to the bisphenol A-based epoxy resin in the standard series. CONCLUSIONS: These cases emphasize that well-known contact allergens may show up from unexpected sources of exposure. Further, it can be a long-lasting, laborious process to detect an occupational contact allergen and cooperation from the patient and the manufacturer of the sensitizing product is essential.


Assuntos
Alérgenos/toxicidade , Ácidos Cicloexanocarboxílicos/toxicidade , Dermatite Alérgica de Contato/etiologia , Dermatite Ocupacional/etiologia , Resinas Epóxi/toxicidade , Óleos Industriais/toxicidade , Metalurgia , Compostos Benzidrílicos , Dermatite Alérgica de Contato/diagnóstico , Dermatite Ocupacional/diagnóstico , Resinas Epóxi/química , Éteres Cíclicos/química , Éteres Cíclicos/toxicidade , Humanos , Masculino , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Testes do Emplastro , Fenóis/toxicidade , Risco
19.
Org Lett ; 4(23): 4105-8, 2002 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-12423097

RESUMO

A new synthesis of attenol A is described. Key features of this work include a crucial silicon tether-aided coupling metathesis step and the use of iodoetherification as an efficient protection method for 1,5-ene-ols. [reaction: see text]


Assuntos
Éteres Cíclicos/síntese química , Silício , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Catálise , Sobrevivência Celular/efeitos dos fármacos , Éteres Cíclicos/toxicidade , Estrutura Molecular
20.
Bioorg Med Chem ; 10(6): 1947-52, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11937353

RESUMO

Series of naphthoquinone thiol-crown ethers had been prepared. The antibacterial, antifungal, and cytotoxic activities of these synthetic naphthoquinone thiol-crown ethers were investigated. All of the compounds tested displayed antibacterial, cytotoxic and antifungal activities. The bis-naphthoquinone thiol-crown ether 7a was the most potent inhibitor among tested analogues against Staphylococcus aureus methicillin resistance with MIC value of 2.68 microM.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Éteres Cíclicos/síntese química , Éteres Cíclicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Antibacterianos , Anti-Infecciosos/química , Anti-Infecciosos/toxicidade , Bactérias/efeitos dos fármacos , Éteres Cíclicos/química , Éteres Cíclicos/toxicidade , Fungos/efeitos dos fármacos , Humanos , Dose Letal Mediana , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/toxicidade , Oxirredução , Relação Estrutura-Atividade , Testes de Toxicidade , Células Tumorais Cultivadas
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