Metabolism of hepatomas of different growth rates in situ and during ischemia.

Abstract

In freeze-clamped rat liver and in hepatomas 9618-A and 5123-D (slower-growing) and 3924-A (rapidly growing), the initial concentrations and time course of changes during ischemia of adenine nucleotides, glucose, lactate, pyruvate, glutamate, 2-oxoglutarate, 3-hydroxybutyrate, acetoacetate, acetyl-CoA, acyl-CoA, glycerides, phospholipid, and total lipid were measured. Initial samples of the tissues were taken under anesthesia within 2 sec after severance of blood vessels, and subsequent samples were obtained during the ensuing ischemia up to 10 min. In hepatomas 5123-D and 3924-A, the initial concentrations of ATP, total adenine nucleotides, and the ATP/ADP ratio were markedly lower than those in livers. During ischemia in liver and in 5123-D and 9618-A, the concentrations of ATP, total adenine nucleotides, and the ATP/ADP ratio decreased while AMP levels increased. In the rapidly growing hepatoma, ischemia did not change ATP or AMP concentrations. The glucose and pyruvate concentrations were lower in all hepatomas than in liver. During ischemia, glucose levels increased in livers and in slow-growing hepatoma 9618-A but were not appreciably altered in the 2 other hepatomas. Initial lactate and glutamate concentrations were much higher in the rapidly growing hepatoma than in liver or in slower growing tumors; the concentration of 2-oxoglutarate was low in all tumors. The ratios of the initial concentrations of lactate/pyruvate and glutamate/2-oxoglutarate increased in hepatomas in parallel with growth rate. Acetyl-CoA, acyl-CoA, total glycerides, phospholipids, and total lipids in 3924-A were 20 to 50% of values observed in liver. In ischemia, the concentrations of acyl-CoA increased in liver but did not change in the hepatoma; the acetyl-CoA, glyceride, phospholipid, and total lipid content did not change either in liver or in 3924-A. The initial concentration of ketone bodies in fed rats was in the same range in the slower-growing tumors as in liver; however, it was low in the rapidly growing tumor. In starvation, the total ketone and 3-hydroxybutyrate concentrations increased over 10-fold in all tissues. Acetoacetate in livers increased 5- to 6-fold during starvation and 13- to 20-fold in the hepatomas. The results also indicate that there are a number of biochemical parameters, including initial lactate level, ability to maintain ATP, and the state of the cytoplasmic and mitochondrial oxidation-reduction couples, that exhibit a correlation with tumor growth rate.