Inhibitory Effect of Disulfiram on Rat Mammary Tumor Induction By N-2-Fluorenylacetamide and on its Metabolic Conversion To N-Hydroxy-N-2-fluorenylacetamide2

Abstract

The effect of an antioxidant, disulfiram (DSF), on the carcinogenicities of N-2-fluorenylacetamlde (2-FAA) and N-hydroxy-N-2-fluorenylacetamide (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 microsomes 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 microsomes with DSF. Measurements of cytochrome P₄₅₀ after pretreatment of rats or microsomes 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 mechanism(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 metabolism.