RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Extracts, essential oils and molecules from Casearia sylvestris have popularly shown pharmacological actions against chronic diseases, as anxiety, inflammation, cancer and dyslipidemia. In the context of antitumoral therapy, we investigated in vitro, ex vivo and in vivo toxicological changes induced by a Fraction with Casearins (FC) and its component Casearin X isolated from C. sylvestris on animal and vegetal cells, and upon invertebrates and mammals. MATERIAL AND METHODS: Cytotoxicity was carried out using normal lines and absorbance and flow cytometry techniques, Artemia salina nauplii, Danio rerio embryos and meristematic cells from Allium cepa roots. Acute and 30 days-mice analysis were done by behavioral, hematological and histological investigations and DNA/chromosomal damages detected by alkaline Cometa and micronucleus assays. RESULTS: FC was cytotoxic against lung and fibroblasts cells and caused DNA breaks, loss of integrity and mitochondrial depolarization on ex vivo human leukocytes. It revealed 24 h-LC50 values of 48.8 and 36.7⯵g/mL on A. salina nauplii and D. rerio embryos, reduced mitotic index of A. cepa roots, leading to cell cycle arrest at metaphase and anaphase and micronuclei. FC showed i.p. and oral LD50 values of 80.9 and 267.1â¯mg/kg body weight. Subacute i.p. injections induced loss of weight, swelling of hepatocytes and tubules, tubular and glomerular hemorrhage, microvesicular steatosis, lung inflammatory infiltration, augment of GPT, decrease of albumin, alkaline phosphatase, glucose, erythrocytes, and lymphocytes, and neutrophilia (pâ¯>â¯0.05). FC-treated animals at 10â¯mg/kg/day i.p. caused micronuclei in bone marrow and DNA strand breaks in peripheral leukocytes. CONCLUSIONS: This research postulated suggestive side effects after use of FC-related drugs, demonstrating FC as antiproliferative and genotoxic on mammal and meristematic cells, including human leukocytes, teratogenicity upon zebrafish embryos, myelosuppression, clastogenicity, and morphological and biochemical markers indicating liver as main target for FC-induced systemic toxicity.
Assuntos
Antineoplásicos Fitogênicos/toxicidade , Casearia , Diterpenos Clerodânicos/toxicidade , Animais , Brasil , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Embrião não Mamífero/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Medicina Tradicional , Meristema/citologia , Camundongos , Cebolas , Testes de Toxicidade , Peixe-ZebraRESUMO
trans-Dehydrocrotonin (t-DCTN), the diterpenoid from Croton cajucara Bentham, exhibits hypoglycemic and hypolipidemic activities, but in high doses is associated with a discrete hepatotoxicity. In the search for measures to mitigate this, pretreatment with the antioxidants N-acetylcysteine and vitamin E has been examined. Mice that received a high dose t-DCTN (100 mg/kg) manifested hepatic damage, as evidenced by significant elevations in serum ALT and AST, and hepatic GSH, and histological alterations, which could be obliterated by pretreatment with vitamin E, but not with N-acetylcysteine, possibly by creating an effective antioxidant balance.
Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Diterpenos Clerodânicos/toxicidade , Vitamina E/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Catalase/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Diterpenos Clerodânicos/antagonistas & inibidores , Interações Medicamentosas , Glutationa/análise , Histocitoquímica , Masculino , Camundongos , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
An EtOH extract of the leaves of Casearia sylvestris afforded new clerodane diterpene, casearin X, together with the known compounds casearins B, D, L, and O, and caseargrewiin F. Casearin X degraded to the corresponding dialdehyde when stored in CDCl(3). The diterpenes isolated were cytotoxic to human cancer cell lines, with caseargrewiin F being the most active and the new clerodane, casearin X, the second active compound with IC(50) values comparable to the positive control doxorubicin. All isolated diterpenes showed lower activities against normal human cells than against cancer cell lines, which might indicate a possible selective action on cancer cells. Casearin X dialdehyde was not cytotoxic to cancer cells indicating that the occurrence of these CO groups at C(18) and C(19) is incompatible with the cytotoxic activity.
Assuntos
Antineoplásicos Fitogênicos/química , Casearia/química , Diterpenos Clerodânicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Diterpenos Clerodânicos/isolamento & purificação , Diterpenos Clerodânicos/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Folhas de Planta/químicaRESUMO
The antiulcerogenic activity of trans-dehydrocrotonin (DHC), a nor-clerodane diterpene isolated from Croton cajucara Benth. (Euphorbiaceae), and its subacute (35 days) toxicity were studied in mice and rats, respectively. For the antiulcerogenic tests, models of gastric ulcers induced in mice by ethanol/HCl or stress were used. In both models, an oral dose of DHC (100 mg/kg) significantly reduced (P < 0.01) the formation of gastric lesions. DHC was also tested for its ability to scavenge free radicals, but no such action was observed in rat liver mitochondria. To assess the subacute toxicity, rats were treated orally with DHC (25, 50 and 100 mg/kg) for 5 weeks. A significant increase in liver weight was observed in male and female rats at highest doses, whereas a significant reduction in plasma alkaline phosphatase and cholesterol levels and an increase in gamma glutamyl transpeptidase were observed only at the highest dose (100 mg/kg) in female rats. DHC caused histopathological alterations in the liver that included a turbid tumefaction, microvacuolar degeneration and nuclear alterations. Despite the beneficial antiulcerogenic activity of DHC, our results suggest that the long-term use of this compound may induce liver damage.