In vitro metabolism of [¹⁴C]methoxychlor in rat, mouse, Japanese quail and rainbow trout in precision-cut liver slices

Abstract

1. The in vitro metabolism of [¹⁴C]methoxychlor (MXC) has been studied using precision-cut liver slices from the Sprague–Dawley male rat, CD-1 male mouse, WE strain male Japanese quail and juvenile rainbow trout (Oncorhynchus mykiss). The results demonstrated integrated phase I and II metabolism of MXC and species differences in the metabolic profiles were observed.

2. In rat liver slice preparations, MXC was rapidly metabolized to bis-OH-MXC by sequential O-demethylation followed by subsequent O-glucuronidation forming bis-OH-MXC glucuronide. No mono-OH-MXC glucuronide was detected. The doubly conjugated metabolite, bis-OH-MXC 4-O-sulphate 4′-O-glucuronide, was also detected as a rat-specific metabolite.

3. Formation of mono-OH-MXC and its glucuronide was the main metabolic pathway in the mouse and Japanese quail. In contrast to the rat, only minor amounts of bis-OH-MXC glucuronide were detected. A reductively dehalogenated metabolite, dechlorinated mono-OH-MXC glucuronide, was observed only in mouse preparations.

4. In rainbow trout, comparative amounts of both mono- and bis-OH-MXC glucuronide were formed as the major metabolites. Unconjugated forms of these metabolites were detected only as minor products.

5. The different metabolic profiles of MXC observed in the four animal species are possibly due to substrate specificity of contributing CYP450 monooxgenase enzyme(s) in different animal species.