Effect of dietary selenium on the metabolism and excretion of 2‐acetylaminofluorene in the rat

Abstract

The metabolism of 2‐acetylaminofluorene (AAF) in vitro and the urinary excretion of a single ip dose of AAF were studied in weanling rats maintained on an Se‐deficient diet or the same diet supplemented with 0.5 ppm Se. Hepatic microsomes isolated from Se‐supplemented rats generated greater amounts of noncarcinogenic phenolic metabolites of AAF than did microsomes from Se‐deficient animals. Under the same conditions, the production of the proximate carcinogenic metabolite N‐hydroxy‐AAF was very low and no difference was detected between the two groups of rats. Microsomes from Se‐deficient rats exhibited moderately higher glucuronyltransferase activity. However, no difference was found between the two dietary groups with respect to hepatic soluble sulfotransferase activity.

Se‐deficient rats excreted slightly more (52 versus 41%) of a single ip dose of [9‐ ¹⁴ C]AAF than did Se‐supplemented rats. This was accounted for by increases in glucuronic acid and sulfuric acid conjugated metabolites as well as by non‐ether‐extractable, water‐soluble metabolites. Both dietary groups excreted equivalent total amounts of unconjugated (free) metabolites. Analyses of ether‐extractable metabolites by high‐performance liquid chromatogrophy revealed that Se‐supplemented animals excreted significantly less N‐hydroxy‐AAF; the decrease was observed in both free and glucuronide fractions of the urine. The pattern of excretion of both free and conjugated phenolic metabolites of AAF was variable; 5‐hydroxy‐AAF appeared in greater quantities in urine from Se‐supplemented rats, while greater amounts of 7‐hydroxy‐AAF and 3‐hydroxy‐AAF were present in urine from Se‐deficient animals.

Taken together, these results suggest that the protective effect of dietary Se against AAF‐induced hepatocarcinogenesis may be due, at least in part, to its ability to inhibit the production of N‐hydroxy‐AAF in vivo. The decreased urinary excretion of this proximate carcinogenic metabolite of AAF reported here and the recently demonstrated protective effect of dietary Se against AAF‐induced hepatic DNA damage lend support to this hypothesis