Quantitative biochemical differences between tumor and host tissue. VI. 6-Aminonicotinamide antagonism of DPN-dependent enzymatic systems.

Abstract

Summary The 755 tumor and six normal tissues of the C57 mouse were analyzed for total DPN concentration and enzymatic capacities to oxidize β-hydroxybutyrate, α-ketoglutarate, and malate. The DPN levels of these tissues had the following order of decreasing concentration: liver, kidney, heart, brain, skeletal muscle, lung, and tumor. These values fell into two separate magnitudes with heart, liver, and kidney having roughly 3 times the concentration of total DPN as did skeletal muscle, lung, brain, and the 755 tumor. The ability to convert β-hydroxybutyrate to acetoacetate, and α-ketoglutarate and malate to citrate, was found to be parallel in all tissues studied, the highest activity being found in the liver. The other tissues showed the following order of decreasing activity: kidney, brain, heart, tumor, lung, and skeletal muscle. The β-hydroxybutyrate system was more sensitive to 6-AN therapy than the system that converts α-ketoglutarate to citrate. Malate conversion to citrate was found to be very resistant to antagonism to 6-aminonicotinamide (6-AN). Therapeutic doses of 6-AN (2 mg/kg for 8 days) markedly inhibited the ability of tumor and lung tissue to convert β-hydroxybutyrate to acetoacetate and α-ketoglutarate to citrate. No other tissues were affected by this level of 6-AN. Increasing the level of drug administered eventually inhibited the β-hydroxybutyrate and α-ketoglutarate systems in brain and liver tissue. At the highest level of 6-AN, no effect was observed in kidney and cardiac and skeletal muscle. In the tissues antagonized, tissues with lower DPN concentration and lower DPN-dependent enzymatic activities were inhibited by low levels of 6-AN. Tissues such as liver which are protected by higher enzymatic and DPN levels required the administration of higher levels of 6-AN before enzymatic inhibition is observed. The concentration of 6-amino-DPN in the 755 tumor and six normal mouse tissues was determined after the administration of a single injection of 6-AN. Liver, kidney, and the 755 tumor synthesized 6-amino-DPN to the same degree. The other tissues were found to have concentrations of 6-amino-DPN in the following order of decreasing activity: brain, lung, heart, and skeletal muscle. The administration of 6-AN caused a marked lowering of the ATP and ADP levels and a large increase in the concentration of AMP in the 755 tumor. Lung tissue under the same conditions exhibited no change in the acid-soluble nucleotide pattern.