Sex hormone-mediated effects on the phase I and phase II metabolism of N-2-fluorenylacetamide. Modulation of 9-hydroxylation.
Sex differences in the phase I (cytochrome P-450-catalyzed hydroxylations) and phase II (conjugations) metabolism of N-2-fluorenylacetamide (2-FAA) by the livers of 50-day-old Sprague-Dawley rats and effects of gonadectomy were determined. The higher level (1.4 times) of cytochrome P-450 in the microsomes of male rats correlated with their 8 and 1.3 times greater capacities to form 9-hydroxy(OH)-2-FAA and 7-OH-2-FAA respectively. One week after gonadectomy, the formation of 9-OH-2-FAA, the major metabolite in the male, was decreased by 70%, whereas in the female it was increased 1.3 times. Treatment of male rats with beta-naphthoflavone (beta-NF) increased the formation of phenolic metabolites and N-OH-2-FAA, but decreased that of 9-OH-2-FAA. The amounts of 9-OH-2-FAA were increased, however, in beta-NF-treated female and gonadectomized male rats. These sex hormone- and beta-NF-mediated differences in the extent of 9-hydroxylation of 2-FAA are discussed in relation to the fluctuations in the levels of specific cytochrome P-450 isozymes. In contrast to the phenolic metabolites and N-OH-2-FAA, 9-OH-2-FAA was a poor substrate for UDP-glucuronyltransferase; this conjugation was not induced by treatment of male rats with beta-NF. Hence, in the presence of male hormones, relatively large amounts of 9-OH-2-FAA were formed and possibly retained in the liver. A role of this alcohol as a potential promoter in hepatocarcinogenesis by 2-FAA is suggested.
Malejka-Giganti
D
D
Laboratory for Cancer Research, Veterans Administration Medical Center, Minneapolis, MN 55417.
Magat
W J
WJ
Decker
R W
RW
D015073:2-Acetylaminofluorene / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D006881:Hydroxyacetylaminofluorene / Q000378:metabolism; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009919:Orchiectomy; D010052:Ovariectomy; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D003573:Cytochrome b Group; D012739:Gonadal Steroid Hormones; D006881:Hydroxyacetylaminofluorene; D019324:beta-Naphthoflavone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D006899:Mixed Function Oxygenases; D014453:Glucuronosyltransferase