Comparative in vitro metabolism of methoxychlor in male and female rats: metabolism of demethylated methoxychlor metabolites by precision-cut rat liver slices.
The in vitro metabolism of demethylated methoxychlor (MXC) metabolites, mono-OH-MXC (including (R)- and (S)-isomers) and bis-OH-MXC (mono- and bis-demethylated MXC, respectively), was conducted using precision-cut liver slices to understand the sex-dependent metabolism of MXC in rats. In the study with bis-OH-MXC, the substrate underwent extensive conjugation producing its glucuronide and glucuronide/sulphate diconjugate, and no significant sex differences were found. On the contrary, the metabolism of mono-OH-MXC appeared to exhibit the sex differences in the metabolic profiles. The bis-OH-MXC glucuronide and glucuronide/sulphate diconjugate were major metabolites in male rat, whereas the mono- and bis-OH-MXC glucuronides predominated in the female. The per cent distribution of the demethylated products (sum of bis-OH-MXC derivatives) was approximately 90% for the male (for both isomers) and 81 (R-) to 56% (S-) for the female. The metabolic profiles in (S)-mono-OH-MXC, which is the predominant enantiomer preferentially produced in MXC metabolism in rats, showed a similar pattern to that of MXC compared with the (R)-isomer. The results indicate that the sex differences in oxidative demethylation of the intermediate, (S)-mono-OH-MXC, could be one of the probable reasons for the sex-dependent metabolism of MXC in rats, and the stereo-structural preference of the contributing demethylase enzymes appear to be involved.
Ohyama
K
K
Institute of Environmental Toxicology, Ibaraki, Japan. ohyama@iet.or.jp
Maki
S
S
Sato
K
K
Kato
Y
Y
D000818:Animals; D005260:Female; D007306:Insecticides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D008731:Methoxychlor / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D042282:Microdissection / Q000379:methods; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D013237:Stereoisomerism
D007306:Insecticides; D010089:Oxidoreductases, N-Demethylating; D008731:Methoxychlor