Document Detail

Nitrogen-stimulated orotic acid synthesis and nucleotide imbalance.
MedLine Citation:
PMID:  1544144     Owner:  NLM     Status:  MEDLINE    
Orotic acid, first discovered in ruminant milk, is an intermediate in the pyrimidine biosynthesis pathway of animal cells. Its synthesis is initiated by the formation of carbamoyl phosphate (CP) in the cytoplasm, with ammonia derived from glutamine. Ureotelic species also form CP in the first step of urea synthesis in liver mitochondria. For that, ammonia is derived from tissue fluid. When there is insufficient capacity for detoxifying the load of ammonia presented for urea synthesis, CP leaves the mitochondria and enters the pyrimidine pathway, where orotic acid biosynthesis is stimulated, orotic acid excretion in urine then increases. Orotic acid synthesis is abnormally high with hereditary deficiencies of urea-cycle enzymes or uridine monophosphate synthase. It is also elevated by ammonia intoxication and during feeding of diets high in protein, high in lysine with respect to arginine, or deficient in arginine, ornithine, and citrulline. Rats fed 1% orotic acid or diets deficient in urea-cycle amino acids develop fatty livers, which has not been demonstrated in other species. Humans consuming 6 g of orotic acid daily have not shown adverse effects. Rats fed 1% orotic acid or arginine-deficient diets also showed more and larger foci positive for gamma-glutamyl transpeptidase and more liver tumors after administration of carcinogens and partial hepatectomy. Orotic acid feeding was also associated with the tendency for development of larger mammary tumors induced by chemical carcinogens in rats and with development of urinary bladder calculi containing high concentrations of orotic acid in mice. Conditions that raise tissue orotic acid change purine-pyrimidine ratios. It is unknown whether tissue orotate concentrations play a role in the recently observed enhanced proliferation of cells in the colon of rats fed high-protein, high-fat diets or in the promotion of chemically induced colon cancer by intrarectal administration of ammonium acetate.
W J Visek
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Cancer research     Volume:  52     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1992 Apr 
Date Detail:
Created Date:  1992-04-15     Completed Date:  1992-04-15     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2082s-2084s     Citation Subset:  IM    
University of Illinois, College of Medicine, Urbana 61801.
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MeSH Terms
Ammonia / metabolism
Carbamyl Phosphate / metabolism
Liver Neoplasms / chemically induced
Milk / metabolism
Orotic Acid / metabolism*,  pharmacology,  urine
Pyrimidines / biosynthesis
Triglycerides / metabolism
Urea / metabolism
Reg. No./Substance:
0/Pyrimidines; 0/Triglycerides; 289-95-2/pyrimidine; 57-13-6/Urea; 590-55-6/Carbamyl Phosphate; 65-86-1/Orotic Acid; 7664-41-7/Ammonia

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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