The Hydrazine Derivative Aminoguanidine Inhibits the Reaction of Tetrahydrofolic Acid with Hydroxymethylarginine Biomolecule

Abstract

Aminoguanidine (AG), a hydrazine derivative is known to inhibit the formation of Advanced Glycosylation Endproducts (AGE) and AG has been proposed as an agent in prophylaxis of diabetic complications. However, treatment with hydrazine produced liver and lung tumors by formation of N7- and O6-methylguanine in the DNA of rodents. The hydrazine derivative, isonicotinic acid hydrazide induced pulmonary tumors in mice. N(G)-hydroxymethyl-arginine (HMA) was synthesized by our research group and it showed anticancer effect against experimental tumors. HMA was found earlier in human blood and urine, and recently in many plants (in fruits and vegetables). We could demonstrate a reaction (pH = 7.5, 37 degrees C, 1h) between HMA and tetrahydrofolate (THF) producing N5,N10-methylene-tetrahydrofolate (CH2-THF), the coenzyme of thymidylate synthase (TS). In model experiments AG proved to react with formaldehyde (HCHO) and to eliminate the C1-fragment of HMA, but not that of CH2-THF. In the presence of AG burst chemiluminescence and a higher speed of the formylation and methylation reactions were found in the AG, HCHO, hydrogen peroxide (H2O2) and L-lysine system than without AG. HMA as a biomolecule is one of the compounds which are responsible for the endogenous HCHO level. The biochemical function of HMA may be the direct supply of C1-fragment for the folate cycle. AG can disturb the above function of HMA. The reaction between AG and HCHO seems to be dangerous for biological systems because of the possible presence of L-lysine and H2O2. The burst chemiluminescence indicates excited molecules with extreme high energy producing uncontrolled formylation and methylation reactions. Considering the results of the experiments with AG its use as a medicament seems to be questionable.