Microsomal metabolism of the carcinogen, N-2-fluorenylacetamide, by the mammary gland and liver of female rats. II. Glucuronidation of ring- and N-hydroxylated metabolites of N-2-fluorenylacetamide

Abstract

We determined UDP-glucuronyltransferse (UDP-GT) activities of hepatic and mammary gland microsomes of female rats with p-nitrophenol and the ring- and N-hydroxylated metabolites of N-2-fluorenylacetamlde (2-FAA) and the effects of hepatic inducers of UDP-GT's on these glucuronidations. Pre-treatment of non-lactating (NL)and lactating (L) rats with β-naphthoflavone (β-NF) significantly increased glucuronidations, of p-nitrophenil, aphenolic metabolites of 2-FAA, especially of 5-hydroxy 2-FAA and also of N-hydrosy-2-FAA by hepatic microsomes. Pre-treatment of L rats with β-NF or 3-methyl cholanthrene (3-MC) significantly incresed glucuronidations of these compounds by mammary gland microsomes suggesting that both liver and mammary gland of L rats possess similar UDP-GT activities. In NL rats, UDP-GT activities of mammary microsomes toward phenols were greater than in L rats, and except for that of 5- and 7- hydroxy-2-FAA, were not inducible with β-NF. The data obtained with L rats, the greater magnitude of stimulation of the hepatic UDP-GT of NL rats by β-NF than by pheno barbital, and the lack of effect of the latter on UDP-GT of mammary microsomes suggested that the phenolic metab olites of 2-FAA and N-hydroxy-2-FAA share chiefly the characteristics of substrates for group 1 UDP-GT activities (i.e., those inducible with β-NF or 3-MC). Neither inducer increased glucuronidation of 9-hydroxy-2-FAA, a relatively poor substrate for UDP-GT of mammary or hepatic micro somes. In contrast to hepatic microsomes which formed considerable amounts of the glucuronide of N-hydroxy-2-FAA, mammary gland microsomes glucuronidated this substrate to a minor extent only. This suggested that glu curonide of N-hydroxy-2-FAA may play a role in systemic, but not in local mammary tumorigenesis by N-hydroxy-2-FAA.