Taurolithocholate-induced intrahepatic cholestasis: potentiation by methyl isobutyl ketone and methyl n-butyl ketone in rats

Abstract

Haloalkane-induced hepatonecrogenesis can be potentiated by the prior administration of methyl isobutyl ketone (MIBK) and methyl n-butyl ketone (MBK). We investigated the possibility that these ketones could potentiate the cholestasis induced by taurolithocholate (TLC) in rats. Daily ketone pretreatment for 3 or 7 days resulted in an enhancement of the diminution in bile flow observed after TLC challenge. When the ketones were administered without TLC challenge, cholestasis was not observed; in fact, slight increases in bile flow did occur. The data suggest that MIBK may be more effective than MBK as a potentiator. Preliminary experiments with 2,5-hexanedione (HD), a metabolite of MBK and a potent potentiator of haloalkane hepatonecrosis, were included in the study. HD appeared to be a less potent potentiator of TLC-induced cholestasis. Although some ketones can potentiate cholestatic as well as hepatonecrogenic reactions, different mechanisms of action appear to be involved in these two phenomena.