Functional Disorders of the Brain Induced by Synthesis of Nucleotides Containing 3-Acetylpyridine

Experiments on the mechanism of pharmacological effects on the central nervous system have led to the discovery of a lack of specificity of certain enzymes in living cells, which may cause biosyntheses of toxic compounds. R. A. PETERS, who observed this phenomenon during his experiments on the toxic effects of fluoroacetate, called it "lethal synthesis". Similar observations can also be made, if antimetabolites of nicotinamide are used, because the lack of specificity of a nucleosidase (NADP-glycohydrolase EC 3.2.2.6) within the endoplasmatic reticulum of the brain cells leads to the biosynthesis of pyridine nucleotides which slow down or completely inhibit the hydrogen transfer between enzyme and substrate of different oxidoreductases. If 3-acetylpyridine is administered to rats in a dose of 80 mg/kg, the formation of nucleotides containing 3-acetylpyridine is the cause of different neurological deficiency symptoms, which include convulsive fits occurring at intervals and permanent disturbances of nervous functions, such as hyperkinesis and ataxic gait. The long lasting deficiency symptoms, which can frequently be shown for more than one year, can be considered as pathobiosis in the sense of the definition given by HEUBNER. In isolated brain microsomes, containing a high nucieosidase activity, the synthesis of the dinucleotide phosphate (3-acetylpyridine adenine dinucleotide phosphate) is greater than that of the dinucleotide in the same time and under the same conditions. Spectrofluorometric examinations of brains of rats which had received 3-acetylpyridine also confirmed this preferred biosynthesis of 3-APADP in vivo. The compound was identified in all the brain sections examined, but the highest values were found in the hippocampus of the rat. During the examination of NADP-dependent enzymes the discovery was made, that probably the pentose phosphate cycle is especially concerned. Thereby lower reduction equivalents than in normal cells are made available for the maintenance of the metabolism during the same time unit. The activity of NADP-dependent enzymes of the pentose phosphate cycle is not the same in all brain regions. During the examination of the glucose 6-phosphate dehydrogenase (EC 1.1.1.49) the highest turnover rates were found in the hippocampus. The kinetics of the malic enzyme (EC 1.1.1.40) discovered by OCHOA are modified in a very peculiar manner, the reaction from malate to pyruvate with 3-APADP acting as hydrogen acceptor being much faster than with the natural coenzyme. The reverse reaction — pyruvate to malate — was greatly slowed down in presence of 3-APADPH2. 3-APADP can also act as inhibitorin presence of NADP, if more than 50% of the natural coenzyme is present as the derivative of 3-acetylpyridine. For the comprehension of the long lasting effects of 3-acetylpyridine on the central nervous system, the diminution of the function of the folic acid reductase (EC 1.5.1.3) is probably of importance. Examinations of the RNA-polymerase (EC 2.7.7.6) of the brain nuclei and mitochondria showed that, in principle, an interference with the function of this system is possible. There are certain indications that the biochemical basis of pathobiotic effects induced by drugs is found in disturbances of the function of the cell nucleic acid systems and of protein synthesis. The analysis of the products of metabolism of 3-acetylpyridine has shown that, except for the product of reduction 3-methylcarbinol, no other metabolite can be made responsible for the causation of the central nervous disturbances.