Dietary nucleotides: A conditional requirement

Abstract

Purines and pyrimidines, either as nucleobases or as polymeric nucleic acids, are not deemed to be essential because de novo synthetic pathways are present for synthesis of these molecules. However, a growing body of evidence suggests that nucleic acids and/or the corresponding purine and pyrimidine bases are conditionally required for normal responses of specific organs or systems of the body. The conditions that expose this heretofore recognized requirement for dietary nucleotides are those under which there is rapid cell replication. Endogenous purines and pyrimidines are synthesized de novo from amino acids and other molecules. Purines are synthesized from glycine, glutamine, asparate, and CO2 formate, while pyrimidines are synthesized from asparate or glutamine, NH3, and C02. Both bases are ribosylated to form nucleosides; these compounds are phosphorylated via PRPP to form nucleotides. These nucleotides can be converted to dior triphosphates, or degraded to nucleosides intracellularly. After removal of the ribose (or deoxyribose) moiety, the pyrimidine nucleobase uracil or cytosine, or the purine nucleobase hypoxanthine, can be further catabolized. Alternately, these bases can be salvaged via use of the substrate PRPP to form the 5 monophosphate by the phosphoribosyltranferases in the cell.’ Previous studies on the fate of dietary purines and pyrimidines suggested limited oral bioavailability compared with a similar parenteral dose.’ The gut has limited adenine synthetic capacity, and dietary purines are largely extracted at the level of the gut. More recent studies suggest a more profound influence of dietary nucleotides on the organism as a whole. LopezNavarro et al.3 demonstrated that rodents fed a nucleotidefree diet showed a significant early decrease in hepatic levels of purine and pyrimidine nucleotides, while a group supplemented with dietary purine and pyrimidine nucleotides demonstrated no such change. This biochemical perturbation was associated with a profound and persistent decrease in hepatic RNA content in rats on the nucleotide-free diet. In contrast, rats supplemented with dietary nucleotides maintained normal hepatic RNA content. The influence of exogenous nucleotides or hepatic RNA levels is greater for the pyrimidine nucleotides. Lopez-Navarro documented that hepatic pyrimidine nucleotide levels are much more vulnerable to dietary restriction. Supplementation of the diet failed to return hepatic pyrimidine nucleotide levels totally to normal, although this may have been due to an inadequate provision of the oral dose of pyrimidine nucleotides. Further confirmation of the critical role of dietary pyrimidine nucleotides was reflected in the recent study of hepatic RNA labeling of hens and mice fed C-labeled algae. Dietary pyrimidines were documented to be significantly incorporated into hepatic nucleotide pools, while virtually no dietary purine nucleosides were used for hepatic nucleic acid synthesis.5 Moreover, dietary uracil, but not cytosine, significantly contributed to hepatic nucleoside synthesis. These authors concluded that pyrimidines, as either the base uracil or as nucleosides, were conditionally essential nutrients. The nutrition experiments described above imply that these profound changes in hepatic RNA content and nucleotide pools will result in suboptimal responses in nucleotide-deprived hosts. The experimental models that document the consequences of these diet-induced hepatic nucleotide levels test three host responses: hepatic regeneration following resection or injury; gut maturation and response to injury; and hostspecific and nonspecific immune responses. Following 70% hepatic resection, a parenteral nutrition regimen containing 10% of amino acid nitrogen as nucleotides and nucleosides significantly enhanced hepatic regeneration.6 Hepatic injury following galactosamine administration was reduced by parenteral provision of a nucleotide/nucleoside mixture.’ These findings suggest that the supply of ribosomal RNA that controls the proliferative response to hepatic resection or chemical injury may be affected by the availability of dietary nucleotides. Moreover, it appears to be the dietary pyrimidine nucleotides or nucleobases that are critical, since the hepatic levels of these substrates correlate best with diet-induced changes in hepatic RNA content. Another rapidly proliferating cell pool of the body appears to be vulnerable to restriction of dietary nucleotides. The content of the small intestinal RNA was significantly reduced in animals deprived of dietary nucleotides or nucleobases.’ This was true in the presence and in the absence of protein in the diet. Furthermore, presence of nucleotides in the diet appeared