RESUMO
Beneficial therapeutic effects of phenolic acids have been proven in various research projects including in vivo and in vitro studies. Gentisic acid (GA) is a phenolic acid that has been associated with useful effects on human health, such as antiinflammatory, antigenotoxic, hepatoprotective, neuroprotective, antimicrobial, and especially antioxidant activities. It is an important metabolite of aspirin and also widely distributed in plants as a secondary plant product such as Gentiana spp., Citrus spp., Vitis vinifera, Pterocarpus santalinus, Helianthus tuberosus, Hibiscus rosa-sinensis, Olea europaea, and Sesamum indicum and in fruits such as avocados, batoko plum, kiwi fruits, apple, bitter melon, black berries, pears, and some mushrooms. This study was undertaken to review the pharmacological effects, pharmacokinetic properties as well as toxicity and pharmaceutical applications of GA.
Assuntos
Gentisatos/farmacologia , Gentisatos/toxicidade , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Aspirina/química , Aspirina/metabolismo , Frutas/química , Gentisatos/isolamento & purificação , Gentisatos/metabolismo , Hibiscus/química , Humanos , Hidroxibenzoatos/metabolismo , Hidroxibenzoatos/farmacologia , Olea/química , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Vitis/químicaRESUMO
Gentisic acid (GA) exhibits antioxidant, anti-inflammatory, and antibiotic activities. This substance can be found in citrus fruits, grapes, olive oil, and peas. Considering that there are few studies in the literature on the toxicity of GA, the present work aimed to investigate its cytotoxic, mutagenic, and antimutagenic activities on HTC cells. GA was diluted in culture medium at the final concentration of 0.08, 0.16, 0.8, 1.6, and 8 µg/mL. The cytotoxicity was determined by the MTT assay and Trypan Blue exclusion method, with methyl methanesulfonate and doxorubicin as positive controls, respectively. The cytokinesis-block micronucleus assay determined the mutagenic/antimutagenic activity with benzo[a]pyrene as positive control. Negative control received culture medium only. GA (0.08-8 µg/mL) was not cytotoxic to HTC cells by the MTT assay nor the Trypan Blue exclusion method as no statistical difference was observed when compared to the control. Concentration of 0.08 and 0.8 µg/mL showed no mutagenic or clastogenic effects, as no significant micronuclei inductions were observed, different from 8 µg/mL, that was mutagenic. Furthermore, none of the concentrations presented an antiproliferative activity. The antimutagenic activity of GA (0.08 µg/mL) was observed at the simultaneous treatment, as it reduced the frequency of micronuclei by 76% (24 h) and 79% (48 h). Although pre- and post-treatments were not statistically different from the mutagen, they reduced the induced-damage by 11% and 21%, respectively. The present study indicated the absence of cytotoxicity and antiproliferative activities of GA, in addition to their antimutagenic/protective effects that may contribute to human health.
Assuntos
Antimutagênicos/farmacologia , Gentisatos/farmacologia , Hepatócitos/efeitos dos fármacos , Mutagênicos/farmacologia , Animais , Antimutagênicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Gentisatos/toxicidade , Hepatócitos/metabolismo , Hepatócitos/patologia , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Mutagênicos/toxicidade , Ratos , Medição de Risco , Fatores de TempoRESUMO
Acetylsalicylic acid (ASA) is known to cause severe hemolytic anemia in some glucose-6-phosphate-dehydrogenase-deficient (G-6-PD-deficient) individuals. To study its mechanism, erythrocytes from an ASA-sensitive patient were transfused into a normal compatible recipient. The administration of 2,5-dihydroxybenzoic (gentisic) acid, a known ASA metabolite with redox properties, to the recipient resulted in a marked decrease in the survival of the patient's erythrocytes. Similar studies with red cells from individuals with A- and Mediterranean variants of G-6-PD revealed no alteration in the erythrocytes' survival. Further studies disclosed that both salicylate and gentisate competitively inhibited the G-6-PD from the ASA-sensitive patient resulting in a marked change in the K(m) for NADP. These drugs also inhibited the A- and Mediterranean variants of G-6-PD. The magnitude of inhibition, however, was comparatively small and not different from that observed with a normal enzyme. The above studies suggested that enzyme inhibition by salicylate and gentisate may play an important role in ASA-induced hemolysis. Such an inhibition would further curtail NADPH regeneration, rendering the cells more vulnerable to oxidants. In this connection, gentisate seems to play a major role in ASA-induced hemolysis for it is both a G-6-PD inhibitor and an "oxidant."
Assuntos
Anemia Hemolítica/induzido quimicamente , Aspirina/toxicidade , Eritrócitos/efeitos dos fármacos , Gentisatos/toxicidade , Deficiência de Glucosefosfato Desidrogenase/sangue , Glucosefosfato Desidrogenase/antagonistas & inibidores , Adolescente , Criança , Envelhecimento Eritrocítico/efeitos dos fármacos , Humanos , MasculinoRESUMO
Female rabbits were injected intraperitoneally (i.p.) with purified flavoglaucin from Aspergillus chevalieri. After 2 h the rabbits were bled and the livers removed for enzyme assays. No changes were found for plasma lactate dehydrogenase (LDH) and its isozymes or liver transketolase (TK) activities. A small but not statistically significant increase was found in plasma glutamate pyruvate transaminase activity. A highly significant increase in plasma glutamic oxaloacetate transaminase activity was observed along with an increase in liver LDH which was, however, not quite significant. The liver also showed some histological evidence of hepatic damage.
Assuntos
Aspergillus/análise , Gentisatos/toxicidade , Alanina Transaminase/metabolismo , Animais , Dimetil Sulfóxido/farmacologia , Isoenzimas , L-Lactato Desidrogenase/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Coelhos , Transcetolase/metabolismoRESUMO
The effects of flavoglaucin from Aspergillus chevalieri (Mangin) Thom et Church on mitochondrial reactions have been investigated to obtain insight into the mode of actions on biomembranes by means of isolated rat liver mitochondria. It was found that flavoglaucin exhibited a strong uncoupling effect on oxidative phosphorylation, enhanced the latent ATPase activity, and elicited a drastic swelling of mitochondria. These reactions led to the exhaustion of ATP in cells, which may be, in part, responsible for its cytotoxicity. Flavoglaucin was toxic to isolated rat hepatocytes causing a karyoklasis, but did not show genotoxicity in hepatocyte primary culture (HPC)/DNA repair test.
Assuntos
Gentisatos/toxicidade , Mitocôndrias Hepáticas/efeitos dos fármacos , Desacopladores/farmacologia , Adenosina Trifosfatases/metabolismo , Animais , Reparo do DNA/efeitos dos fármacos , Técnicas In Vitro , Membranas/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Ratos , Ratos Endogâmicos ACIRESUMO
Metabolic products are often more toxic than their pharmacological parent compounds. Therefore, the acute and chronic effects of the main metabolites--salicylic acid (SAL), gentisic acid (GEN), and o-hydroxyhippuric acid (HDP)--of acetylsalicylic acid (ASA), the active ingredient in Aspirin and many other pharmaceuticals, were assessed using standard (Daphnia magna) and autochthonous (Daphnia longispina) cladocerans. The sequence of decreasing levels of acute and chronic toxicity of ASA metabolites to daphnids was GEN > SAL > HDP. HDP did not present acute toxicity, but chronic exposures enabled the production of abnormal neonates and, in particular, egg abortion. Thus, reproduction was the end point most susceptible to HDP. On the other hand, SAL and GEN induced changes in the normal patterns of reproduction and growth of both species. In general, D. longispina was more sensitive than was D. magna, although the population growth of the autochthonous species was superior under SAL exposures than that of the standard test species. Although the concentrations that were determined to have a toxic effect were above the levels detected in aquatic environmental samples, exposure to low levels of pharmacologically active substances for a duration longer than the test period may induce changes in nontarget organisms.