THE JOURKIL OF B~omcxca~ CIIEMISTRY

The metabolism of a histidine load after the differential induction of the hepatic histidine catabolic enzymes, histidase, and cytosolic histidine-pyruvate aminotransferase, and the functional significance of these inductions, has been studied in the intact rat and in the isolated perfused rat liver. Histidase was induced by feeding an 80% casein diet, while the aminotransferase (as well as histidase) was induced by injecting a combination of glucagon and cortisol for several days. The rate of 14C02 production after a loading dose of 750 mg of histidine containing [U-i4C]histidine was approximately 6 times greater in rats that had been previously treated with a high protein diet or hormones than in control rats fed a 9% casein diet. Concomitant with this increased oxidation, liver, plasma, and muscle histidine concentrations returned to normal within 6 to 9 hours in the experimental rats, while still remaining elevated at 12 hours in the controls. Urinary excretion of imidazolepyruvate increased 6-fold in rats previously treated with hormones, while the plasma (especially) and liver pools of this metabolite increased significantly within 2 hours after feeding histidine, but returned to normal by 9 hours. Muscle imidazolepyruvate showed a slight, but insignificant increase after 6 hours. A high correlation was observed among histidase activity, the amount of histidine removed from the perfusate and i4C02 production from (UJ4C]histidine, in liver perfusion experiments in which the liver was presented with a large load of histidine (520 mg/lOO ml of perfusate). In addition, the accumulation of imidazolepyruvate in the perfusate closely paralleled the aminotransferase activity. In the isolated perfused liver, disappearance of histidine from the perfusate and 14C02 production from histidine were also dependent on the concentration of histidine. These results indicate that the metabolism of histidine is dependent on the pathway induced. In addition, the enzyme inductions occurring as a result of prior dietary or hormonal treatment are functionally significant, and represent adaptive responses that are important since the capacity of the normal metabolic machinery to respond to a substrate load is limited.