Metabolic Interaction of n‐Hexane and Methyl Ethyl Ketone in vitro in a Head Space Rat Liver S9 Vial Equilibration System

Abstract: Methyl ethyl ketone pretreatment induced rat liver cytochrome P450 and increased significantly the in vitro metabolism of n‐hexane and the formation of 2,5‐hexanedione in rat liver S9. No significant changes were, however, found in the levels of the intermediate metabolites 2‐hexanol, 2,5‐hexanedioI or methyl n‐butyl ketone. Methyl ethyl ketone added in vitro to untreated (non‐induced) liver S9 inhibited in a non‐competitive pattern the metabolism of n‐hexane and decreased significantly and in a dose‐dependent way the levels of methyl n‐butyl ketone and 2,5‐hexanedione. When methyl ethyl ketone and n‐hexane were added in vitro to in vivo methyl ethyl ketone pretreated (induced) liver S9, the significant increase in the formation of 2,5‐hexanedione was maintained, an increase which was only to a minor extent influenced by the in vitro addition of methyl ethyl ketone. These findings are in agreement with an in vivo induction by methyl ethyl ketone of key enzyme(s) in a generally minor metabolic pathway for the conversion of n‐hexane to 2,5‐hexanedione in rat liver, a pathway which is not influenced by the presence of methyl ethyl ketone itself. The results obtained in this study indicate that the head space equilibration technique is well suited for screening studies of metabolic interactions between organic solvents.