Folate catabolism in tumour-bearing rats and rats treated with methotrexate

Abstract

The metabolism of (2-14C) + (3',5',7,9-3H) folic acid was studied in normal rats, tumour-bearing rats and rats treated with methotrexate (MTX). The experiments were designed to investigate changes in the catabolism and folate. The breakdown of folate to scission products was again demonstrated to be a normal phenomenon. Catabolites excreted included p-acetamidobenzoate, p-acetamidobenzoyl-L-glutamate, 3H2O, urea and a number of pterins. The catabolic process was decreased in the presence of a tumour and increased by the administration of MTX. MTX also led to the excretion of 4 additional radioactive pterins not found in normal urine. The possible mechanisms of folate breakdown are discussed with reference to the point of action of MTX.

Folate metabolism in man: the effect of malignant disease

“…If the radioactivity not recovered in the urine or faeces is retained in the tissues, man excretes a higher percentage of the tissue folates as scission products than the rat (Table IV). This is consistent with the suggestion that catabolism proceeds via oxidative cleavage on the C9-NIO bond (Murphy et al, 1976;Saleh et al, 1981 since the hepatic NAD/NADH ratio is higher in man than rat (R. A. Harris, personal communication).…”

“…Intestinal malabsorption of folate is not usually associated with neoplasia (Chanarin, 1979) and, by analogy with the rat, the remaining radioactivity is presumably taken up into tumour tissue (Saleh et al, 1981). This is supported by the inverse correlation between the approximate tumour mass and urinary radioactivity.…”

“…This apparent decrease in the catabolism of tissue folate in the presence of a tumour has also been observed in rats, and it has been suggested that it is due to the anoxia of solid tumours, and to the more reducing conditions prevailing in the cytosol of tumour cells (Saleh et al, 1981).…”

“…The 14C-labelled catabolite has not been identified. It eluted from both columns in the position of metabolite B which has been recently reorted in rat urine (Saleh et al, 1981). Table IV summarizes the relative distribution of the major metabolites appearing in the various urine samples of both groups of patients.…”

“…Folate deficiency is associated with malignant disease (Blakley, 1969;Chanarin, 1979) but no detailed comparative metabolic studies have been carried out in man. Catabolism of folate in the rat has recently been shown to be reduced in the presence of a tumour (Saleh et al, 1981). Therefore the metabolism of a mixture of 14C-and 3H-labelled folic acid was studied in control patients and in patients with malignant disease in order to observe any metabolic variations which may have diagnostic or therapeutic applications.…”