PRETRANSLATIONAL ACTIVATION OF CYTOCHROME-P450IIE DURING KETOSIS INDUCED BY A HIGH-FAT DIET

Ethanol-inducible cytochrome P450 (P450IIE) is reported to be induced by ketosis. In the present study, the effects of a high fat diet on P4 50IIE induction and the relationship between ketone body concentration and P450IIE induction were studied by the following: 1) measurement o f the activity of aniline hydroxylase, 2) immunoblot analysis for P450 IIE protein, and 3) Northern blot analysis for P450IIE mRNA. The enzym e activities (aniline hydroxylase) in hepatic and renal microsomes wer e elevated about 2-3-fold by feeding with a high fat diet for 3 days. The increases in enzyme activities were also accompanied by 3-fold inc reases in immunoreactive P450IIE protein and its mRNA. In contrast, no differences were observed for the catalytic activities of N-alkoxyres orufin dealkylases or the amounts of immunoreactive P450IA and P450IIC , indicating a specific induction of P450IIE by high fat feeding. Furt hermore, the increases in the levels of P450IIE mRNA correlated positi vely (r = 0.73) with plasma concentrations of acetoacetate and beta-hy droxybutyrate but not with that of acetone, which induces P450IIE with out changing its mRNA level. Our data thus indicated that P450IIE indu ction during the ketosis of a high fat feeding appears to be due to pr etranslational activation and that is similar to the induction mechani sm of fasted and diabetic animals.