Comparative in vitro metabolism of the suspected pro-oestrogenic compound, methoxychlor in precision-cut liver slices from male and female rats

Abstract

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.

Key words::

• Sex differences
• enantioselective metabolism
• metabolic activation
• oestrogenic responses
• oxidative demethylation
• conjugation