ROLE OF REDUCING EQUIVALENTS FROM FATTY-ACID OXIDATION IN MIXED-FUNCTION OXIDATION - STUDIES WITH 2-BROMOOCTANOATE IN THE PERFUSED-RAT-LIVER

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Abstract
Mixed-function oxidation of p-nitroanisole in isolated perfused livers from fasted rats was studied in the presence and absence of 2-bromooctanoate, an inhibitor of the .beta.-oxidation of acyl CoA compounds. These experiments were designed to test the hypothesis that reducing equivalents from fatty acid oxidation may play a role in drug metabolism in the fasted state. Complete inhibition of ketogenesis, as indicated by .beta.-hydroxybutyrate and acetoacetate production, was achieved with the addition of 0.6 mM 2-bromooctanoate to the perfusate. This concentration of 2-bromooctanoate had no effect on p-nitroanisole O-demethylation measured in isolated microsomes but diminished maximal rates of p-nitroanisole O-demethylation by 78% in perfused livers of fasted, phenobarbital-treated rats. No inhibition of p-nitroanisole O-demethylation was seen in perfused livers from fed rats. Intracellular concentrations of ATP, NADH, glutamate, .alpha.-ketoglutarate and isocitrate decreased significantly in the presence of 2-bromooctanoate; O2 uptake also decreased by about 50%. By inhibiting endogenous acyl CoA oxidation, 2-bromooctanoate diminished .beta.-oxidation of fatty acids, thereby decreasing the supply of NADH for the generation of ATP. This decreased the synthesis of NADPH, an obligatory cofactor for drug metabolism. 2-Bromooctanoate also decreased the concentration of intermediates which act through substrate shuttle act mechanisms to move reducing equivalents from the mitochondrial into the extramitochondrial space. The decrease in mixed-function oxidation observed when .beta.-oxidation of fatty acids is inhibited with 2-bromooctanoate probably is due to diminished availability of mitochondrial reducing equivalents for the generation of cytosolic NADPH.

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