Inhibitory Induction Effect of Disulfiram on Rat Mammary by N-2-Fluorenylacetamide and on Its Conversion to N-Hydroxy-N-2-fluorenylacetamide

The effect of an antioxidant, disulfiram (DSF), on the carclnogenlcltles of N-2-fluorenylacetamlde (2-FAA) and Nhydroxy-N-2-fluorenylacetamlde (N-OH-2-FAA) was examined. DSF given In a diet at a concentration of 0.9% for 1 week before and throughout the carcinogen treatment (0.1 mmol/kg 3 times a week for 4 weeks) reduced the Incidence of mammary tumors Induced with 2-FAA by 50% and extended the mean latency period of malignant tumors from 5 to 10 months. By contrast, DSF had no effect on mammary carcinogenesis by N-OH-2-FAA. Consistent with these results was the demonstration of the Inhibitory effect of DSF on the first step of metabolic activation of 2-FAA, I.e., Nhydroxylation. N-Hydroxylatlon of 2-FAA was significantly InhibIted In hepatiC mlcrosomes of untreated and 2-FAA-treated male and female rats by DSF given orally. A similar Inhibition was shown In vitro after preincubation of hepatic mlcrosomes with DSF. Measurements of cytochrome P450 after pretreatment of rats or mlcrosomes with the inhibitor showed no appreciable changes In the hemoprotein content. It was concluded, therefore, that the inhibitory effect of DSF on N-hydroxylation of 2-FAA Is accomplished through mechanlsm(s) other than depression of the cytochrome P450 level. Because both 2-FAA and DSF bind to cytochrome P450 producing a type I spectrum, DSF may Interfere with the binding of 2-FAA and thus alter Its metabollsm.-JNCI 64: