Comparative in vitro metabolism of the suspected pro-oestrogenic compound, methoxychlor in precision-cut liver slices from male and female rats.
The in vitro metabolism of [14C]methoxychlor (MXC), a suspected pro-oestrogenic compound, by male and female Fischer rats (F344) was compared in precision-cut liver slices. The results demonstrated time-dependent metabolism of MXC with integrated phase I and II reactions, and the sex differences were detected in the metabolic profiles. In liver slices from male rats, MXC was metabolized to bis-demethylated MXC (bis-OH-MXC) by sequential O-demethylation followed by subsequent O-glucuronidation. The doubly conjugated metabolite, bis-OH-MXC 4-O-sulphate 4'-O-glucuronide was additionally produced. In the case of the female rat, the glucuronides of both mono- and bis-OH-MXC were formed as the main metabolites, and the mono-OH-MXC glucuronide appeared to be specific to the female rat. The ratios of bis-/mono-demethylated metabolite, which include the amounts of corresponding conjugates, were approximately 95/5 for the male rats and 40/60 for the female. These results imply that demethylation to the intermediate metabolite, (S)-mono-OH-MXC, is a key step for the sex-dependent metabolism of MXC in the rats. The phase I metabolites produced were extensively conjugated with D-glucuronic acid in both male and female rats.
Ohyama
K
K
The Institute of Environmental Toxicology, Mitsukaido, Japan. ohyama@iet.or.jp
Maki
S
S
Sato
K
K
Kato
Y
Y
D000818:Animals; D004967:Estrogens / Q000493:pharmacokinetics*; D005260:Female; D008658:Inactivation, Metabolic; D007306:Insecticides / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008731:Methoxychlor / Q000493:pharmacokinetics*; D042282:Microdissection; D009924:Organ Culture Techniques; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors
D004967:Estrogens; D007306:Insecticides; D008731:Methoxychlor