RESUMEN
A possible role of oxidative stress in producing acute toxicity in rat liver by aromatic amines and nitroarenes was tested. Oxidative stress was assessed by measuring the excretion of oxidized glutathione (GSSG) into the bile in isolated perfused livers and in female Wistar rats with cannulated bile ducts. The liver perfusion system was calibrated with t-butylhydroperoxide (t-BH) and menadione. The minimal concentration in the perfusate of t-BH necessary to observe a significant effect was 18 microM for 5 min. It was calculated that rat liver is able to cope with an extra production of about 70 nmol GSSG per min and g liver before GSSG is excreted into bile. No effect was observed when 2-aminofluorene, 2-acetylaminofluorene (AAF), trans-4-aminostilbene, and trans-4-acetylaminostilbene were added to the perfusate at 50 microM for 20 min. Moreover, 2-aminofluorene, trans-4-aminostilbene, 2-nitrofluorene and trans-4-nitrostilbene did not increase GSSG excretion when administered simultaneously with effective concentrations of t-BH. AAF was not acutely toxic, blood transaminases and lipid peroxidation were not increased with AAF doses as high as 1 mmol/kg. Since the dose rate of aromatic amines, like AAF, in feeding studies for tumor formation is about 100 times below that examined in the isolated perfused livers, it is highly unlikely that oxidative stress is generated by metabolites able to undergo redox cycling and that reactive oxygen contributes to acute toxic effects.
Asunto(s)
Aminas/farmacología , Muerte Celular/efectos de los fármacos , Hígado/efectos de los fármacos , Estrés Oxidativo , 2-Acetilaminofluoreno/farmacología , 2-Acetilaminofluoreno/toxicidad , Animales , Bilis/metabolismo , Femenino , Fluorenos/farmacología , Fluorenos/toxicidad , Glutatión/metabolismo , Hígado/metabolismo , Perfusión , Peróxidos/farmacología , Ratas , Ratas Wistar , Estilbenos/farmacología , Estilbenos/toxicidad , Vitamina K/farmacología , terc-ButilhidroperóxidoRESUMEN
It has been demonstrated in several model systems that tumors arise in a multistage process. Carcinogenic aromatic amines are complete carcinogens, which usually produce tumors in typical target tissues without any additional treatment. The tissue specificity, however, cannot readily be explained by genotoxic effects, and the role of secondary effects is not well understood. Promotional pressure on initiated cells can be produced by endogenous factors but also by the chemical itself. Comparison of the effects on rat liver of 2-acetylaminofluorene (AAF) and trans-4-acetylaminostilbene (AAS) provides some evidence that initiating and promoting properties of these chemicals can be separated. AAS is a strong initiator in rat liver but seems to lack promoting activity; AAF is a less efficient initiator but has tumor promoting properties. The results obtained so far indicate that promoting pressure is not produced by the acute, cytotoxic effects of AAF. It is therefore concluded that nongenotoxic, possibly receptor-mediated effects are involved.