title: Estrogenic activity of an environmental pollutant, 2-nitrofluorene, after metabolic activation by rat liver microsomes.
abstract: In this study, the metabolic activation of 2-nitrofluorene (NF) to estrogenic compounds was examined. NF was negative in estrogen reporter assays using estrogen-responsive yeast and human breast cancer cell line MCF-7. However, the compound exhibited estrogenic activity after incubation with liver microsomes of 3-methylcholanthrene-treated rats in the presence of NADPH. Minor estrogenic activity was observed when liver microsomes of untreated or phenobarbital-treated rats were used instead of those from 3-methylcholanthrene-treated rats. When the compound was incubated with the liver microsomes of 3-methylcholanthrene-treated rats in the presence of NADPH, 7-hydroxy-2-nitrofluorene (7-OH-NF) was formed as a major metabolite. However, little of the metabolite was formed by liver microsomes of untreated or phenobarbital-treated rats. Rat recombinant cytochrome P450 1A1 exhibited a significant oxidase activity toward NF, affording 7-OH-NF. Liver microsomes of phenobarbital-treated rats also enhanced oxidase activity toward NF. In this case, 9-hydroxy-2-nitrofluorene was formed. 7-OH-NF exhibited a significant estrogenic activity, while the activity of 9-hydroxy-2-nitrofluorene was much lower. These results suggest that the estrogenic activity of NF was due to formation of the 7-hydroxylated metabolite by liver microsomes.
authors.affiliation: Graduate School of Biomedical Sciences, Programs for Pharmaceutical Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
authors.forename: Seigo
authors.initials: S
authors.lastname: Sanoh
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Yoshihara
authors.forename: Nariaki
authors.initials: N
authors.lastname: Fujimoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
mesh_terms: D000393:Air Pollutants / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D004958:Estradiol / Q000378:metabolism*; D045166:Estradiol Congeners / Q000493:pharmacokinetics; D005449:Fluorenes / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000393:Air Pollutants; D045166:Estradiol Congeners; D005449:Fluorenes; C019499:2-nitrofluorene; D004958:Estradiol; D010634:Phenobarbital