FOOD RESTRICTION AND STIMULATION OF MONOOXYGENATION OF P-NITROANISOLEIN PERFUSED-RAT-LIVER

This study assessed the affects of food restriction on the metabolism of model monooxygenase substrates in the perfused rat liver. Female Sp rague-Dawley rats had access ad lib. to a Purina 5001 nonpurified diet (control) or were given 65% of the intake of controls for 3 weeks. Li vers were perfused with oxygenated Krebs-Henseleit buffer using a non- recirculating system, and the rates of monooxygenation of p-nitroaniso le and 7-ethoxycoumarin were measured. The results indicate that food restriction stimulated p-nitroanisole O-demethylation from 2.9 +/- 0.2 to 4.6 +/- mu mol/(g.hr) when saturating concentrations of p-nitroani sole were infused. concomitantly, the ratio of beta-hydroxybutyrate to acetoacetate (B/A) and the rates of ketogenesis (B + A) were increase d significantly by food restriction. Further, p-nitroanisole (200 mu m ol/L) increased hepatic malate concentration nearly 3-fold in liver ex tracts from food-restricted rats. However, infusion of either a low co ncentration of p-nitroanisole (50 mu mol/L) or 7-ethoxycoumarin (200 m u mol/L) did not alter these parameters. On the other hand, food restr iction did not alter rates of monooxygenation in isolated microsomes s upplemented with excess NADPH. Taken together, these data support the hypothesis that high concentrations of p-nitroanisole increased monoox ygenation in food-restricted rats by stimulating fatty acid oxidation, which elevates the mitochondrial NADH/NAD(+) ratio. This, in turn, in creases the availability of reducing equivalents in the form of NADPH by a malate-pyruvate exchange system, leading to increased drug metabo lism.