RESUMEN
The existence of fenitrothion (FNT) in the soil, water, and food products has harmful effects on non-target organisms. Therefore, this study was conducted to evaluate the hepatotoxic, nephrotoxic and neurotoxic effects of FNT and the possible ameliorative effect of N-acetylcysteine (NAC), a precursor of intracellular GSH, on FNT-induced toxicity. For this purpose, thirty-two adult male albino rats were allocated into control group and groups treated with NAC (200â¯mg/kg), FNT (10â¯mg/kg) and FNTâ¯+â¯NAC via gastric tube daily for 28 days. FNT intoxication significantly reduced food intake, water intake, body weight, and body weight gain and altered the expression of phase I and phase II xenobiotic-metabolizing enzymes-cytochrome P450 (CYP1A1) and glutathione S-transferase (GSTA4-4). In hepatic, renal and brain tissues, FNT induced oxidative stress, hepatopathy, nephropathy, and encephalopathy, and significantly increased pro-inflammatory cytokines. Furthermore, FNT exposure significantly elevated the level of hepatic and renal injury biomarkers and significantly inhibited the brain acetylcholinesterase activity. Co-administration of NAC with FNT modulated most of these altered biochemical, oxidative and inflammatory markers and restored the xenobiotic-metabolizing enzymes expression and histological structures. Our study indicated the involvement of oxidative damage, inflammation, and alteration of xenobiotic-metabolizing enzymes expression in FNT-induced toxicity and revealed that they were significantly improved by NAC co-treatment. These findings suggest that NAC administration might protect against FNT-induced toxicity in non-target organisms, including humans.
Asunto(s)
Acetilcisteína/farmacología , Antioxidantes/metabolismo , Encéfalo/efectos de los fármacos , Fenitrotión/toxicidad , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Biomarcadores , Encéfalo/metabolismo , Creatinina/sangre , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Regulación de la Expresión Génica , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
The cancer chemopreventive activity of quinoxaline derivatives 1-20 has been evaluated by studying the inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation. The quinoxaline derivatives 1-20 showed inhibitory effect on EBV-EA activation without cytotoxicity on Raji cells. All compounds exhibited dose dependent inhibitory activities, most of them showed significant activity at 1000 mol ratio/12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 7 and 9 exhibited stronger inhibitory effects on the EBV-EA activation than that of the representative control, oleanolic acid, at the highest measured concentration. In addition, compounds 7-10 showed potent and selective inhibition of human tyrosine kinase (TRK) in liver cancer HepG2 and breast cancer MCF-7 cell lines similar to the positive control, doxorubicin.
Asunto(s)
Antígenos Virales/metabolismo , Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Quinoxalinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Quinoxalinas/síntesis química , Quinoxalinas/química , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-ActividadRESUMEN
In this work, the benzimidazole-pyrrole conjugates 6a-h and benzimidazole-tetracycles conjugates 12-14 were prepared. The cytotoxicity of the compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 was tested against lung cancer cell line A549. Compound 6b exhibited higher activity than the bis-benzoxazole natural product (UK-1), the standard. The tested 4g,h, 6a-h, 10 and 12-14 exhibited remarkable cytotoxicity activity against breast cancer cell line MCF-7 with higher activity than tamoxifen. Furthermore, compound 4h was found to be also more potent than doxurubicin. The antitumor promotion activity of synthesized compounds 4g,h, 6a-h, 10 and 12-14 has been estimated by studying their possible inhibitory effects on EBV-EA activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds, the inhibitory activities of compounds 8, 13 and 14 demonstrated strong inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation without showing any cytotoxicity on the Raji cells and their effects being stronger than that of a representative control, oleanolic acid. Moreover, the molecular docking of the new compounds into plasminogen activator (uPA) receptor has been in correlation with the antitumor activity. All synthesized compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 were docked into same groove of the binding site of the native co-crystalized (4-iodobenzo[b]thiophene-2-carboxamidine) ligand (PDB code:1c5x) for activity explaination. Compounds 4h, 6b and 13, giving the best docking results, were further studied to estimate their effect on the level of uPA using AssayMax human urokinase (uPA) ELISA kit. In case of A549 cell line, compound 6 exhibited similar activity to MMC, and for MCF-7 cell line, compound 4h exhibited similar activity to doxorubicin, in inhibiting the expression of uPA.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/fisiología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Células MCF-7 , Modelos Moleculares , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad , Tetraciclinas/síntesis química , Tetraciclinas/química , Tetraciclinas/farmacología , Activación Viral/efectos de los fármacosRESUMEN
The reaction of o-phenylene diamine and ethyl oxamate is reinvestigated and led to 3-aminoquinoxalin-2(1H)-one rather than benzimidazole-2-carboxamide as was previously reported. The structure of the obtained quinoxaline has been confirmed by X-ray. The anti-tumor activity of synthesized quinoxalines 1-21 has been evaluated by studying their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds 1-21, compounds 12, 8, 13, 18, 17 and 19, respectively, demonstrated strong inhibitory effects on the EBV-EA activation without showing any cytotoxicity and their effects being stronger than that of a representative control, oleanolic acid. Furthermore, compound 12 exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. The result of the present investigation indicated that compound 12 might be valuable as a potent cancer chemopreventive agent. Moreover, the molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.