Inhibition of Paranitroanisole and Antipyrine Monooxygenation in Isolated Rat Hepatocytes by Compounds Interacting with Mitochondrially Related Carbohydrate Metabolism

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Abstract
The monooxygenation of paranitroanisole (PNA) and antipyrine (AP) were measured in isolated rat hepatocytes incubated with compounds interacting with mitochondrially related carbohydrate metabolism. Phenylpyruvate, an inhibitor of pyruvate carboxylase, reduced the rate of PNA and AP metabolism to about 60 and 20%, respectively, in hepatocytes both from fasted and fed rats. Inhibition of amino acid transaminase with aminooxyacetate, decreased the metabolism of both PNA and AP to 60–70% of control values in hepatocytes from fasted rats, whereas this effect was not seen in fed rats. n‐Butylmalonate, an inhibitor of mitochondrial malate/phosphate exchange, had only minimal effects on PNA and AP monooxygenation in both the nutritional states. The simultaneous presence of glyoxylate and pyruvate, known to inhibit the NADPH specific isocitrate dehydrogenase, reduced the metabolism of both PNA and AP in hepatocytes from fasted rats to about 60 and 35% of control values respectively, while the effect was not so marked in hepatocytes from fed rats. The metabolism both of PNA and of AP in hepatocytes from fasted rats was reduced to 50–60% of control values with the addition of NH4Cl. This effect could be blocked either by incubating the hepatocytes with pyruvate or by using hepatocytes isolated from fed rats. The addition of various carbon intermediates generally reduced the effect of the inhibitors used. Phenobarbital‐treatment did not change the effects observed with cells from uninduced animals. The inhibitors did not alter PNA or AP metabolism in microsomal incubations, and therefore most likely reduced the monooxygenation in intact cells by affecting NADPH generation pathways.