No abstract

2-(3-Methyl-cinnamyl-hydrazono)-propionate (MCHP) is a new compound which effectively lowers the blood glucose level in guinea pigs. 0.04 mmol/l MCHP inhibited glucose formation from lactate, pyruvate and alanine, but not from dihydroxyacetone in the perfused guinea pig liver. In the presence of both hexanoic acid and alanine, 0.04 mmol/l MCHP did not effect hepatic gluconeogenesis. Gluconeogenesis was probably reduced by an inhibition of the pyruvate carboxylase: The pattern of hepatic metabolite concentrations indicated a block between pyruvate and the triose phosphates. The intrahepatic concentration of acetyl-CoA was consistently decreased. The decrease of the acetyl-CoA concentration could be explained by an influence of MCHP on the fatty acid oxidations, which occurred at the carnitine palmitoyl transferase (CPT) step. This hypothesis is supported by the fact that a medium chain fatty acid not requiring CPT reversed the inhibition of gluconeogenesis by MCHP. From all results reported it is concluded that transamination and oxidative phosphorylation were not effected to a degree relevant for the inhibition of gluconeogenesis by 0.04 mmol/l MCHP.

The subcellular distribution of ii tyrosine aminotransferase inactivating factor in rat liver has been investigated. Most of its activity is associated with plasma membranes, with minor amounts in mitochond ria and endo plasma tic ret icul um.The factor is also found in kidney and inactivates the enzyme reversibly in presence of cysteine, most likely by modification of -SH groups.ATP counteracts this inactivation only, when crude enzyme extracts are inactivated by purified subcellular fractions or when the purified enzyme is inactivated in presence of liver or kidney cortex homogenates.The relationship of this inactivation to reported different forms of the enzyme has been investigated. Form I of three different forms, that can be obtained by hydroxyl-apatite chromatography, is readily inactivated, form I11 can be partly converted to form I by incubation in presence of purified plasma membranes.The relationship of these findings to a possible multistep mechanism in the turnover of the enzyme is discussed.

The hydrazone-compound 2-(3-methyl-cinnamylhydrazono)-propionate (MCHP) significantly lowered the blood glucose concentration in fasted guinea pigs and rats. A significant decrease of blood glucose levels was observed in fasted guinea pigs already after an intraperitoneal injection of 20.5 mumol/kg MCHP, while much higher doses (about 1000 mumol/kg) were necessary to produce a hypoglycemic effect in the fasted rat. After oral administration MCHP (82.0 mumol/kg) significantly decreased the blood glucose concentration in guinea pigs. Furthermore MCHP caused a dose-dependent increase of plasma free fatty acid concentrations in guinea pigs and rats. In addition, MCHP decreased the concentrations of blood ketone bodies, plasma cholesterol and intrahepatic acetyl-coenzyme A in the guinea pig. All of these findings appear to be due to a reduced fatty acid utilization in the presence of MCHP resulting presumably in an intramitochondrial deficiency of acetyl-CoA. At hypoglycemic effective doses the intramitochondrial and cytoplasmatic redox ratios as well as the hepatic ATP/ADP ratio were not influenced by MCHP in fasted guinea pigs. Even at large doses (123 mumol/kg) MCHP decreased the activity of monoamino oxidase in guinea pigs only by less than 15%. Furthermore MCHP showed under our experimental conditions no relevant influence on the activity of various liver enzymes in plasma, the plasma concentration of creatinine, the plasma triglyceride-glycerol level and on the intrahepatic triglyceride-glycerol concentration of fasted guinea pigs. It is concluded that MCHP meets basic requirements for a potential oral antidiabetic agent.

The rate of mitoehondrial carnitine-carnitine exchange mediated by carnitine acylcarnitine translocase was measured by föllowing the uptake of L-[methyl-14 C]carnitine. It was demonstrated that the hypoglycaemic compound 2-(3^methyKcinnamyl-hydrazono)-propionate causes a concentration-dependent decrease in the rate of the translocase-mediated transport of carnitine in guinea pig liver mitochondria. Apparent initial infhix rates were decreased by 20% at 0.3 mmol/1 2-(3-methyl-cinnamyl-hydrazono)-propionate, 38% at 0.5 mmol/1, and 75% at 2.0 mmol/1 of this compound. This finding may explain the previously observed inhibitory effects öf this substance on long^chain fatty acid oxidation, ketone body production and gluconeogenesis. ™ "Among these hydrazpnes, 2-(3^methyl-cinnamyl-hyHydrazpnes of pyruvate exert a powerful hyppgly-drazpnp)-propionate is a powerful hypoglycaemic agcaemic effect in varioüs labprätpry aiiimals (1-6). ent, the metabolic effects of which have already been In addition to theif potential usefulness for the treat-studied in considerable detail. Studies on the mode ment of diabetes, such substances facilitate studies of action revealed that 2-(3-methyl-cinnamyl-hydraon the interrelationship betwen metabolic pathways, zpno)-prppionate inhibits gluconeogenesis in guinea provided that their mode of action is known. pig liver (7,8). Furthermore in the rat and in the guinea pig an increase in the concentration of free .fatty acids in the plasma and a decrease in blood 0 Preliminary results of this study were presented at the third ketone body concentration was observed, which meetingoftbeGermanAsspciation for the Studyof the Liver pointed to an Inhibition of long-chain fatty acid oxm Hannover 1987 (abstract: Z. Gastroenterologie (1987) 25. idation (5)e It has been suggested that this Inhibition 2 ) For previous publications see I.e. (3-5), (8), (25). by 2-(3-methyl-cinnamyl-hydrazono)-propionate oc-