Microsomal metabolism of the carcinogen, N-2-fluorenyl-acetamide, by the mammary gland and liver of female rats. II. Glucuronidation of ring- and N-hydroxylated metabolites of N-2-fluorenylacetamide.
We determined UDP-glucuronyltransferase (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-fluorenylacetamide (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 beta-naphthoflavone (beta-NF) significantly increased glucuronidations, of p-nitrophenol, the phenolic metabolites of 2-FAA, especially of 5-hydroxy-2-FAA, and also of N-hydroxy-2-FAA by hepatic microsomes. Pre-treatment of L rats with beta-NF or 3-methyl-cholanthrene (3-MC) significantly increased 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 beta-NF. The data obtained with L rats, the greater magnitude of stimulation of the hepatic UDP-GT of NL rats by beta-NF than by phenobarbital, and the lack of effect of the latter on UDP-GT of mammary microsomes suggested that the phenolic metabolites 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 beta-NF or 3-MC). Neither inducer increased glucuronidation of 9-hydroxy-2-FAA, a relatively poor substrate for UDP-GT of mammary or hepatic microsomes. 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 glucuronide of N-hydroxy-2-FAA may play a role in systemic, but not in local mammary tumorigenesis by N-hydroxy-2-FAA.
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002250:Carbon Radioisotopes; D005260:Female; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000032:analysis; D006900:Hydroxylation; D066298:In Vitro Techniques; D007774:Lactation; D008321:Mammary Glands, Animal / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D002250:Carbon Radioisotopes; D005965:Glucuronates; D009596:Nitrophenols; D019324:beta-Naphthoflavone; D015073:2-Acetylaminofluorene; D014453:Glucuronosyltransferase; C024836:4-nitrophenol; D010634:Phenobarbital