Factors affecting the Metabolic Production of Methylguanidine

Abstract

1. Methylguanidine administered orally to normal volunteers was almost completely recovered in the urine, indicating that it is absorbed in the gastrointestinal tract and is not converted into other compounds. In normal persons at least, its urinary output therefore corresponds to its metabolic production rate plus the amount ingested. 2. In normal persons, diets based on foods not containing methylguanidine (e.g. vegetarian, protein-free and milk-egg) caused a fall in the urinary output of methylguanidine as compared with the output of the same subjects on a free diet. Conversely, higher amounts of methylguanidine were excreted on a diet rich in broth and in boiled beef, which contain large amounts of methylguanidine formed from the oxidation of creatinine, caused by boiling. 3. Oral administration of creatinine to normal volunteers induced an immediate and marked increase in urinary excretion of methylguanidine, and the ingestion of [methyl-14-C]creatinine by uraemic patients was followed by the urinary excretion of labelled methylguanidine. These findings indicate that creatinine is partly converted into methylguanidine in both normal and uraemic subjects and accounts for the high metabolic production of methylguanidine in patients with renal failure, in whom the body pool of creatinine is high. 4. Creatinine, incubated at 38 degrees C for 24 h in Krebs bicarbonate solution (pH 7-38) through which was bubbled oxygen with 15% carbon dioxide, was partially oxidized to methylguanidine. This raises the possibility that even in vivo such a conversion may occur "non-enzymatically".

Comparison of Methylguanidine Production from Creatinine and Creatol in vivo

“…Therefore, MG is undoubtedly a toxin causing a variety of uremia-like symptoms. Although the route of MG production remains controversial, the idea that Cr is the precursor of MG is predominant [4][5][6][7][8], We have previously investigated time-course changes in MG pro duction after Cr administration, and found that most of the produced MG is excreted into urine in normal rats [9,10]. Therefore, in the present study, the amount of MG produced from Cr was compared with that from creatol, using the level of urinary MG excretion as an index.…”

Studies on the Precursor of Methylguanidine in Rats with Renal Failure

“…Conversion of MG from Cr has been demonstrated by l4CH r Cr administration in nor mal rats by Perez and Faluotico [11] and in healthy human subjects and patients with renal failure by Gonella et al [12]. Recently, Nagase and co-workers [13] demonstrated the production of MG from Cr, using normal rats and isolated liver cells.…”

“…In this connection, we have previously observed, in a comparative study using normal rats and those with adenine-induced renal failure, that the level of MG increased gradually in the blood, various tissues and urine with progression of renal failure, and that a high quantity of MG was accumulated in skeletal muscle after intraperitoneal administration of this substance, showing dose-dependent toxicity [8-10J. The route and site of MG production have also been studied by many researchers, and creatinine (Cr), guanidinoacetic acid (GAA) and arginine (Arg) have been cited as probable precursors, and the liver, kidney and skeletal muscle as the organs responsible for MG production [11][12][13][14][15][16][17]. However, there has been no consensus of opinion on this issue.…”

Production of Methylguanidine from Creatinine in Normal Rats and Rats with Renal Failure

“…At present, the prevailing hypothesis is that the precursor of MG is creatinine (Cr) [3][4][5][6][7], but few reports have documented any comparison between the amount of MG produced from Cr under normal condi tions and that in renal failure. We previously produced a rat model of adenine-induced renal failure and reported various physiologicobiochemical and histological find ings obtained using it [8][9][10][11][12], With regard to variations in MG, it was found in this model that the level of MG in blood and various tissues and the level of MG excretion into urine increased gradually along with the progression of renal failure.…”