The metabolism of pyruvate in the tricarboxylic acid cycle of developing mammalian liver.

Previous work has indicated that much of the biochemical maturation of the mammalian liver takes place around the time of birth (l-6). In the present study of this critical period, we have investigated the mode of pyruvate utilization in the tricarboxylic acid cycle. Pyruvate enters the tricarboxylic acid cycle in two ways, as acetyl coenzyme A and as a dicarboxylic acid. In the following experiments, the apportionment of pyruvate entering the tricarboxylic acid cycle between acetyl coenzyme A and dicarboxylic acid was estimated in vivo by determining the relative distribution of isotope in glutamic acid after injection of nn-alanine-2-C14. The method is based on the observation that the position of isotopic labeling in glutamic acid by pyruvate-2-Cl4 depends on the route of entry of pyruvate into the tricarboxylic acid cycle (7, 8). The mode of pyruvate utilization in the tricarboxylic acid cycle was studied at various stages of development in guinea pig liver. The stages were chosen to coincide with different phases in the metabolism of glycogen and fat (9, 10). In guinea pig liver, the functional state of the glycogen and fat stores around the time of birth may be divided into three phases. First, before the 57th day of gestation, glycogen is present only in traces, and the fat concentration is stabilized at about twice the level of the maternal liver; second, from the 57th day until birth (68 days), both the glycogen and fat concentrations gradually increase to values 3 and 4 times those found in the mother; and third, during the first few days after birth, glycogen and fat are rapidly depleted. The apportionment of pyruvate in the tricarboxylic acid cycle between acetyl coenzyme A and dicarboxylic acid was studied in 57and 68-day-old fetuses, when the fetuses are at the beginning and the height of glycogen and fat storage; in 4-hour-old newborns when the rate of fat and glycogen depletion is highest; at 30 hours after birth when the fat concentration is still falling rapidly; at 10 days after birth when the fat concentration is still falling but at a very reduced rate; and at 30 days after birth when the fat and glycogen concentrations have stabilized at normal adult values.