Effects of acetone administration on drug-metabolizing enzymes in mice: presence of a high-affinity diethylnitrosamine de-ethylase

Abstract

Treatment of CD1 mice with acetone raised activities of hepatic microsomal p-nitrophenol hydroxylase, ethoxycoumarin de-ethylase, acetone hydroxylase and diethylnitrosamine de-ethylase (DENd) several-fold. P-450IIE1-linked acetone hydroxylase showed the highest inducibility. In microsomes from acetone-pretreated mice the cytochrome b5 and P-450 content was nearly doubled and their electrophoretic profile showed induction of a protein of Mr 53 000, probably P-450IIE1. Liver phase II enzymes were not affected by acetone treatment. Kinetic analyses of DENd were performed in control or acetone-induced microsomes and K m and V max were determined. Two distinctly apparent K m values (0.56 and 20.3 mM) were observed for DENd of control microsomes and at least 3 apparent K m values (0.05, 0.51, 8.4 mM) were observed in acetone-induced microsomes. Thus, acetone administration to mice induces a high-affinity form of DENd which can be important in vivo at low diethylnitrosamine (DEN) exposure as this enzyme functions when DEN concentration is below 0.1 mM.