Potentiation by methyl isobutyl ketone of the cholestasis induced in rats by a manganese-bilirubin combination or manganese alone.

Haloalkane-induced hepatonecrogenesis can be potentiated by the prior administration of methyl isobutyl ketone (MIBK). In a previous study, MIBK was shown to potentiate the cholestasis induced by taurolithocholate in rats. We investigated the possibility that this ketone could potentiate the cholestasis induced by a combination of manganese and bilirubin (Mn-BR) or by manganese alone in rats. Dosages varying from 1.88 to 15 mmol/kg MIBK were administered once, 18 hr prior to the administration of the cholestatic Mn-BR combination. The cholestatic effect of the manganese-bilirubin combination is enhanced with dosages of MIBK of 3.75 mmol/kg and more. Daily ketone pretreatment for 3 days resulted in an increased response to the cholestatic challenges of either Mn-BR or Mn alone. MIBK per se is devoid of cholestatic properties, since the bile flow measured prior to the cholestatic challenge is not decreased and in some cases is significantly greater than that from vehicle-pretreated animals. These results show that MIBK can potentiate cholestatic as well as necrogenic forms of hepatotoxicity.