RESUMEN
Initiating activities of 26 chemicals were investigated in an in vivo 5 week initiation assay model with evaluation of the induction of glutathione S-transferase placental form (GST-P) positive foci as end-point lesions. With the five genotoxic hepatocarcinogens (diethylnitrosamine, dimethylnitrosamine, 2-acetylaminofluorene, N-bis(2-hydroxypropyl)-nitrosamine and safrole) and 11 genotoxic non-hepatocarcinogens, (2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide, benzo[a]pyrene, N-butyl-N-(4-hydroxybutyl)nitrosamine, 7,12-dimethylbenz[a]anthracene, 1,2-dimethylhydrazine, N-ethyl-N-hydroxyethylnitrosamine, 3-methylcholanthrene, N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine, 4-nitroquinoline 1-oxide and 8-hydroxyquinoline), the numbers of GST-P positive foci were significantly higher than in the controls. On the other hand, the mutagenic non-carcinogens (quercetin, p-phenylenediamine dihydrochloride, 2-chloroethanol and 6-hydroquinoline) did not cause a significant increase. Similarly, non-genotoxic hepatocarcinogens of the hepatopromotor class and promotors which target organs other than the liver did not induce GST-P positive foci. The specificity was thus remarkable. Moreover, regardless of the target organ, mutagenic carcinogens were detected by this in vivo 5 week initiation assay, which therefore constitutes a powerful method for screening for carcinogenic potential, especially in the initiation stage of carcinogenesis.
Asunto(s)
Carcinógenos/toxicidad , Neoplasias Hepáticas Experimentales/inducido químicamente , Hígado/efectos de los fármacos , Mutágenos/toxicidad , Animales , Transformación Celular Neoplásica/efectos de los fármacos , Gutatión-S-Transferasa pi , Glutatión Transferasa/biosíntesis , Isoenzimas/biosíntesis , Hígado/enzimología , Neoplasias Hepáticas Experimentales/enzimología , Masculino , Modelos Biológicos , Ratas , Ratas Endogámicas F344RESUMEN
As a part of the ILSI-HESI Alternative to Carcinogenicity Testing (ACT) program, we performed a 26-week carcinogenetic study of nonmutagenic drug, ampicillin (ABPC) in Tg-rasH2 mice. ABPC was given to Tg-rasH2 mice (0, 350, 1000, 3000 mg/kg, p.o.) and Non-Tg mice (0, 3000 mg/kg, p.o.) daily for 26 weeks. As a positive control, a single dose of MNU was administered once to Tg-rasH2 mice (75 mg/kg, i.p.). In this study, Tg-rasH2 mice did not demonstrate any increases in tumor development in response to ABPC. Thus, ABPC had no carcinogenicity in the 26-week carcinogenesis study in Tg-rasH2 mice or in a 2-year carcinogenesis study in B6C3F1 mice.
Asunto(s)
Ampicilina/toxicidad , Carcinógenos/toxicidad , Neoplasias Experimentales/inducido químicamente , Penicilinas/toxicidad , Administración Oral , Ampicilina/administración & dosificación , Ampicilina/farmacocinética , Animales , Peso Corporal/efectos de los fármacos , Pruebas de Carcinogenicidad , Carcinógenos/administración & dosificación , Carcinógenos/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Genes ras , Longevidad/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Ratones Noqueados , Neoplasias Experimentales/patología , Penicilinas/administración & dosificación , Penicilinas/farmacocinéticaRESUMEN
Focal disturbed laminar architecture in cerebellar vermis was observed in 25 out of 100 (25%) males, and 25 out of 100 (25%) females of BrlHan: WIST@Jcl rats. The cortical molecular and granular layers were haphazardly distributed around the primary and/or secondary fissures. The stellate and basket cells positively stained with parvalbumin immunohistochemistry were observed exclusively in the separated molecular layer. Purkinje cells were found at the boundary between the molecular and the granular layers. Glial fibrillary acid protein (GFAP) immunohistochemistry revealed disarranged fibers of the Bergman glial cells. Based on the incidence of this spontaneous cerebellar lesion, it was presumed to be related to certain genetic factors of this rat strain.