Pathways of pyruvate metabolism in the mammary gland

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Abstract
In order to correlate the utilization of added substrates with their effect on respiration, lactating mammary gland slices (rat, rabbit, and sheep) were depleted of preformed substrates by aerobic incubation without added substrates, prior to incubation in the Warburg apparatus. By this treatment the high endogenous respiration was reduced by 50-70%; the ability of the depleted tissue to metabolize glucose or pyruvate was often impaired or lost, but was completely restored by the addition of fumarate in low concns. Small amts. of citric acid accumulated when depleted mammary gland slices were incubated with fumarate and pyruvate. Fumarate reversed the inhibition of respiration caused by malonate. The above observations suggest that the citric acid cycle is operative in the mammary gland. In phosphate saline the O2 consumption of mammary tissue metabolizing pyruvate was increased by 50-100% by 2 x 10-4 [image] 2,4-dinitrophenol (DNP), without a corresponding stimulation of pyruvate utilization. DNP thus increases the ratio O2 consumed/pyruvate metabolized. Pyruvate is metabolized with high R.Q. which is reduced to 1.2-1.3 by DNP. These findings, and manometric measurements of gaseous exchanges in bicarbonate saline, indicate that pyruvate is oxidized more completely in the presence of DNP than in its absence. Although 2 x 10-4 [image] DNP accelerated respiration in the presence of pyruvate, it was inhibitory in the presence of glucose. Lower concns. of DNP (to 5 x 10-5 [image]) stimulated respiration when glucose was metabolized. DNP therefore appears to affect carbohydrate metabolism in 2 ways: by influencing the glycolytic breakdown of glucose to pyruvate; by influencing the metabolic fate of pyruvate. It is concluded that pyruvate is metabolized by mammary tissue by 2 pathways; oxidation via the Krebs cycle and synthetic reactions. About 2 mol. of pyruvate appear to be utilized in synthetic reactions for every mol. of pyruvate oxidized. Inhibition of synthetic reactions by DNP increases the fraction of pyruvate oxidized and thus increases the overall O2 consumption and the O2/pyruvate ratio.