Effects of acetone administration on drug-metabolizing enzymes in mice: presence of a high-affinity diethylnitrosamine de-ethylase.
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 Km and Vmax were determined. Two distinctly apparent Km values (0.56 and 20.3 mM) were observed for DENd of control microsomes and at least 3 apparent Km 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.
Puccini
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Istituto di Mutagenesi e Differenziamento, CNR, Pisa, Italy.
Fiorio
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Longo
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Gervasi
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PG
D000096:Acetone / Q000494:pharmacology*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004052:Diethylnitrosamine / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010078:Oxazines / Q000494:pharmacology; D010088:Oxidoreductases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology
D007093:Imidazoles; D010078:Oxazines; D011720:Pyrazoles; D000096:Acetone; D004052:Diethylnitrosamine; C031280:pyrazole; C014180:resorufin; C029899:imidazole; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C029225:diethylnitrosamine deethylase