H. Grahn

Influence of D-galactosamine upon the NAD-metabolism in rat liver.

After application of D-galactosamine a hepatitis develops in the rat liver. This can be prevented by different agents, including tryptophan. Yet it has not been possible to give definitive conclusions about the mechanism of galactosamine hepatitis. In this paper we report about the influence of galactosamine on the NAD metabolism. D-galactosamine inhibits the NAD synthesis initiated by nicotinamide in normal and adrenalectomized animals. The NAD synthesis from tryptophan is prevented in normal animals, in adrenalectomized ones however there is an increase of NAD in the presence of D-galactosamine reduces the activity of the ADPR transferase. Inhibitors of the ADPR transferase prevent the galactosamine hepatitis. From the results presented we conclude that the ADPR transferase plays an important role in the development of the galactosamine hepatitis.

5-Methylcytosine content in different organs of the mouse and rat, several tumors and in mice embryos

1. The content of 5-methylcytosine of the DNA of 11-day old mice embryos was compared with that of the DNA of different plasmocytoms. 2. Furthermore the DNA content was determined in different transplantable tumors and normal organs of the rat and the mouse. 3. By the aid of liquid chromatography significant differences could be demonstrated in the content of 5-methylcytosine of the DNA of BALB/c-mice or NMRI-mice and the DNA of the plasmocytom MOPC 104 E and MOPC 141, but not in the case of MOPC 321. 4. Clear differences could be observed with restriction enzymes: the DNA of all the plasmocytoms studied is more digested with Hpa II and Hha I than the DNA of the embryos. This is not the case however with MSP I. 5. The DNA of three transplantable tumors tested contains less 5-methylcytosine than the one of the liver kidney of the mouse and the rat. This was confirmed with restriction enzymes too.

Influence of ethanol upon the introduction of tyrosine aminotransferase in liver, upon the NAD content in liver and brain, and upon the activity of glutamate oxalate aminotransferase and glutamate pyruvate aminotransferase in the serum of rats

The influence of ethanol, tryptophan, nicotinamide and methionine upon the activity of glutamate oxalate aminotransferase and glutamate pyruvate aminotransferase in serum as well as the induction of tyrosine aminotransferase in the liver, and of NAD+ + NADH in liver and brain are described. After oral application of 6 g/kg ethanol, the activities of the examined enzymes and the concentrations of NAD+ + NADH in the brain as well as in the liver did not change over a period of 8 hr. Administration of L-methionine lead--as is the case with DL-tryptophan--to a decrease of the NAD+ + NADH-concentration in the brain. A simultaneous application of nicotinamide, DL-tryptophan, L-methionine of l-methylnicotinamide together with ethanol caused a significant increase of the tyrosine aminotransferase induction in adrenalectomized animals. Ethanol reduced the activity of the ADPR transferase in the nuclei of rat liver cells.

Influence of N-methylformamide on the development, the NAD synthesis, and the activity of the ADPR transferase of rat embryos

When N-methylformamide is administered to rats on the 11th day of pregnancy approximately 50% of the fetuses are resorbed and a reduced weight of the developed animals is found in comparison to the controls on the 21th day (delivery by Caesarian section). The toxic effect is increased by using nicotinamide and methionine. If a combination of these substances is employed practically all fetuses are resorbed. Tryptophan, however, has a considerably protective influence. N-Methylformamide has no influence on the NAD-synthesis induced by nicotinamide or tryptophan. It does, however, inhibits the activity of the ADPR transferase.

Methylation of Deoxyribonucleic Acid in Regenerating Rat Liver

In double label pulse experiments DNA methylation was compared to DNA synthesis after partial hepatectomy. 24 hours after the operation the highest 14C-thymidine incorporation rates were found as well as the highest 5-methylcytosine labelling derived from (3H-methyl) -methionine. However, synthesis was much more elevated than DNA methylation. Applying Endoxan DNA methylation is reduced to a significantly higher extent than DNA synthesis. Our results indicate that DNA methylation occurs not only combined with DNA synthesis.

Short time action of antirheumatic substances on the liver of rat. Protective effect of tryptophan + methionine

1. A large number of drugs, including some antirheumatic substances, cause liver damage. 2. Only a little information is available, so far, on the causes of such damage and their prevention. 3. From studies on a number of antirheumatic drugs as to their effect upon the liver, three categories could be differentiated: (a) large effect (b) low effect (c) no effect. 4. Judging from our results, the liver damage is induced via a disturbance of the NAD-adenoribosylation metabolism.

Influence of ethanol, nicotinamide, orotic acid and caffeine upon the induction of tyrosine aminotransferase, the NAD content and the ADPR transferase activity in rat liver☆

Chronic uptake of ethanol leads to irreversible damage of liver cells. Until now the cause of this alteration is unknown. To get more information experiments presented in this paper were performed. Contrary to normal fed animals the enzyme tyrosine aminotransferase (TAT) can be induced by ethanol in starved rats. Orotic acid induces the TAT at a dose of 500 mg/kg. This effect is enhanced to some extent by ethanol. Ethanol increases the minor effect of 50 mg/kg caffeine on TAT induction markedly. Only 500 mg/kg nicotinamide (NA) enhances TAT activity. Here ethanol has a minor stimulatory effect. A combination of nicotinamide with orotic acid or with caffeine leads to substances with a higher effect on TAT induction. Besides nicotinamide and its derivatives only caffeine changes the NAD+ + NADH content of the liver. Ethanol and caffeine reduce the activity of the ADPR transferase. The results indicate that the effect of ethanol might be due to interference with NAD-adenoribosylation metabolism.

Influence of dexamethasone phosphate upon the DNA- and the nad-metabolism of concanavaline a stimulated t-lymphocytes

1. Glucocorticoids have a decisive function in the immune system. In this paper, special attention is paid to the DNA and the NAD metabolism in T-lymphocytes of mice stimulated by Con A under the influence of dexamethasone phosphate. 2. Nicotinamide increases the incorporation of [3H]thymidine into the DNA of T-cells in dependence on the concentration. There is a similar but less pronounced effect with 1-methylnicotinamide. 3. Dexamethasone phosphate even at 10(-9) M inhibits the incorporation of [3H]thymidine into DNA. 4. The incorporation of [3H]thymidine into the DNA is reduced after preincubation of the T-cells with 6-aminonicotinamide or with 3-acetylpyridine. 5. Dexamethasone phosphate decreases the content of NAD in the T-cells. 6. The activity of the ADPR transferase increases after addition of Con A. Presence of nicotinamide stimulates the effect of Con A on this enzyme. This is not the case with 1-methylnicotinamide. The enzyme is inhibited drastically by dexamethasone phosphate. 7. It may be concluded that the NAD-adenoribosylation metabolism is markedly influenced by the mitogen Con A and by dexamethasone phosphate.

Influence of oxypangam upon the induction of tyrosine aminotransferase, the NAD content and the ADPR transferase activity in several organs of the rat☆

Oxypangam is a substance applied therapeutically against a number of diseases, such as chronic liver damages, angina pectoris, and psychosomatic disturbances. The mode of action of oxypangam has not yet conclusively been described. The only well-known properties of this substance are its intensive methylating and lipolytic effects. The present paper serves to elucidate the influence of oxypangam on the induction of the tyrosine aminotransferase, on the NAD content and on the activity of the ADPR transferase in the liver. Our studies showed that in normal animals, increasing doses of oxypangam support the induction of tyrosine aminotransferase. Up to a concentration of 100 mg/kg oxypangam enhances also the induction of tyrosine aminotransferase by tryptophan. In both cases, however, it does not work in adrenalectomized animals. Under the influence of oxypangam the NAD content of the liver remained unchanged, while the activity of the ADPR transferase was influenced only slightly.

Influence of streptozotocin upon the induction of tyrosine aminotransferase, the content of NAD and of 5-methyl cytosine in rat liver.

The antibiotic, streptozotocin, has carcinostatic, carcinogenic, and diabetogenic properties. Moreover, it is capable of inducing the enzyme tyrosine aminotransferase in a permanent line of rat liver cells. In the present publication, the effects of streptozotocin upon the induction of tyrosine aminotransferase, NAD synthesis, and methylation of DNA in different organs were analyzed in vivo. If administered alone, streptozotocin slightly induced tyrosine aminotransferase. The induction of tyrosine aminotransferase caused by tryptophan or nicotinamide was inhibited by streptozotocin. Streptozotocin reduced the NAD content of the liver. NAD synthesis induced by tryptophan was reduced by streptozotocin, while that induced by nicotinamide was enhanced. DNA methylation in the form of 5-methyl cytosine was not influenced by streptozotocin.