Urinary Excretion of Formiminoglutamic Acid by Human Subjects after Antifolic Acid Therapy1

Abstract

In the accompanying paper a sensitive and specific enzymatic method is described for the measurement of formiminoglutamic acid (1). In this paper data are presented on the application of this method for the assay of formiminoglutamic acid in the urine of a variety of patients.Formiminoglutamic acid is an intermediate in histidine metabolism, and requires tetrahydrofolic acid for its further metabolism. Previous results (2-5) have demonstrated that the urinary excretion of this compound is markedly increased in folic acid-deficient rats. Formiminoglutamic acid has also been reported (6, 7) in the urine of several patients receiving folic acid antagonists, although the techniques available for these studies were relatively cumbersome and inaccurate.Using the enzymatic procedure for the assay of formiminoglutamic acid, we have found that small amounts of this compound can often be detected in the urine of adults and children. A marked elevation in formiminoglutamic acid excretion was noted after amethopterin (methotrexate) therapy in children with acute leukemia. METHODS

Phenylalanine Metabolism and Folic Acid Antagonists*

“…The reaction may be considered, therefore, part of a degradative pathway for excessive phenylalanine, as well as a part of several synthetic pathways which include tyrosine. Folic antagonists also inhibit the degradation of the amino acid histidine by blocking the metabolism of formiminoglutamic acid (FIGLU) (22). The excretion of this intermediate has been used as a test of folic deficiency or folic antagonism.…”

A Method for the Determination of Formiminoglutamic Acid in Urine1

“…Duplicate assays usually agree within 0.001 micromole, even when the determinations are carried out with different enzyme and tetrahydrofolic acid preparations. No inhibitory effects are observed with rat urine or with human urine, even after amethopterin (methotrexate) treatment (21).…”

Urinary Urocanic Acid in Man: The Identification of Urocanic Acid and the Comparative Excretions of Urocanic Acid and N-Formiminoglutamic Acid After Oral Histidine in Patients With Liver Disease

“…The formimino group is then transferred to tetrahydrofolic acid, a reaction catalyzed by formiminoglutamic acid transferase, ultimately to enter the pool of metabolically active one-carbon fragments as a derivative of N-10-formyltetrahydrofolic acid. The excretion of FiGlu in folic acid deficiency (11,15), pernicious anemia (15,16), or folic acid antimetabolite therapy (13,21) is believed to be due to a lack of tetrahydrofolic acid receptor for the formimino group.…”

“…FiGlu excretion has been studied in recent years in patients with folic acid deficiency (10)(11)(12) and treated with folic acid antagonists (13). It has been found that such patients, particularly when given loading doses of histidine, excrete increased amounts of this metabolite in the urine.…”