3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties

Abstract

A protein fraction containing gamma-butyrobetaine hydroxylase (sp.act. 1.54 mU/mg) was isolated from the rat liver by differential precipitation with ammonium sulphate. 3-(2,2,2-Trimethylhydrazinium)propionate (THP), a noncompetitive enzyme inhibitor, when administered orally to rats for 10 days (150 mg/kg) elicited a reduction in myocardial free carnitine and long-chain acyl carnitine content by 63.7 and 74.3%, respectively. This reduction in free carnitine concentration causes a suppression of the free fatty acid oxidation, as measured by the production of 14CO2 and ketone bodies. The inhibition of fatty acid oxidation is particularly manifest when their metabolism is stimulated by feeding a fat-rich diet to the animals or in fasting rats. The inhibition of fatty acid metabolism at the stage of activation (acyl carnitine formation) can account for the cardioprotective effect of THP, which is assessed by its ability to prevent a decrease in ATP level and myocardial energy charge as well as to prevent a rise in creatine phosphokinase and lactic dehydrogenase (myocardium-specific isozyme) activity in rat blood serum in response to isoproterenol and epinephrine. Regulation of the carnitine-dependent fatty acid metabolism in ischaemia is a pathogenetically justified approach to pharmacological treatment of ischaemic myocardium. In its biochemical mechanism, THP significally distinguishes itself from other known inhibitors of fatty acid oxidation.