Abstract
The role of erotic acid as a precursor in the biosynthesis of pyrimidine nucleotides is well established (2). However, little is known about the mechanism by which erotic acid produces a grossly fatty liver in rats when it is fed as 1% of their diet (3). Livers from erotic acid-fed rats contain high levels of triglycerides (4)) cholesterol (5), and acid-soluble uridine nucleotides but depressed levels of adenine and pyridine nucleotides (6). Furthermore, in such livers there is an inhibition of pyridine nucleotide synthesis (7, 8), cholesterol biosynthesis (5), and lipoprotein secretion (9, lo), the latter being an apparent cause of hepatic fat accumulation. These effects can be prevented or rapidly reversed by addition of a small amount of adenine to the diet (8, 10-12). A deficiency of hepatic adenine nucleotides may be a primary factor in the chain of erotic acid-induced effects. Several compounds which depress hepatic adenine nucleotide concentrations, such as ethionine (13), 4-aminopyrazolopyrimidine (14), and others (15), produce changes in liver similar to those produced by erotic acid. It is not known why erotic acid feeding depresses the concentration of adenine nucleotides. The suggestion has been made (6, 7) that because large amounts of PPribose-P are utilized for conversion of erotic acid to uridine 5’-phosphate, other PP-ribose-P-requiring biosynthetic reactions, including purine biosynthesis, may be inhibited. Therefore, it was of interest to determine the rate of purine biosynthesis in livers of erotic acid-fed rats. To this end, incorporation in viva of formate-14C and of glycine-2-14C into liver purines was determined. Incorporation into liver protein and lipid was also measured, primarily to detect any erotic acid-induced changes in the endogenous hepatic pools of formate and glycine. It was found that erotic acid, rather than being inhibitory, stimulated incorporation of 14C into acid-soluble as well as into nucleic acid purines. Furthermore, this effect of erotic acid was completely nullified by the addition of small amounts of adenine to the diet.
Highlights
Incorporation of Formate-14C into Hepatic Purines-Intravenous administration of formate-i4C resulted in rapid labeling of hepatic acid-soluble adenine and guanine (Fig. 1)
To be able to conclude from studies of formate-14C and glycineW incorporation that purine biosynthesis is accelerated, it must be assumed that experimental conditions are not altering the size of the available pools of glycine and formate with which the radioactive tracer is diluted
Incorporation in viva of 1% into hepatic purines, protein, and lipids was determined at intervals of 5 min to 24 hours following intravenous administration of glycine-2-l*C or formate-W to young rats
Summary
Administration of Labeled Formate-W and Glycine-W4C-Male Sprague-Dawley rats (NIH colony) weighing 55 to 60 g were fed a complete basal diet (R-l) [16] for 4 days. Groups of animals received a dietary supplement of 1 y0 erotic acid or 1 y0 erotic acid plus 0.25% adenine sulfate. After 1 to 5 days, as indicated, between 8 to 10 a.m., sodium formate-% (20 mC per mmole, New England Nuclear) or glycine-2-l% (1.6 mC per ,umole, New England Nuclear) was administered intravenously (femoral vein) under light ether anesthesia. Per 100 g of body weight, 38 PC of labeled compound in 0.3 ml of 0.95%. The radiochemical purity of the sodium formate and glycine was 96% or greater as determined by chromatography on paper or by isotope dilution after addition of carrier and two recrystallizations
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