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Effect of Glycine on the Induction of Orotic Aciduria and Urinary Bladder Tumorigenesis in the Rat

Department of Pathology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and Emo State University, School of Biological Sciences, PMB 2000, ETTI, Emo State, Nigeria

Ezio Laconi

Department of Pathology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and Emo State University, School of Biological Sciences, PMB 2000, ETTI, Emo State, Nigeria

Samuel E. Abanobi

Department of Pathology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and Emo State University, School of Biological Sciences, PMB 2000, ETTI, Emo State, Nigeria

Prema M. Rao

Department of Pathology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and Emo State University, School of Biological Sciences, PMB 2000, ETTI, Emo State, Nigeria

Srinivasan Rajalakshmi

Department of Pathology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and Emo State University, School of Biological Sciences, PMB 2000, ETTI, Emo State, Nigeria

Dittakavi S. R. Sarma

Department of Pathology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and Emo State University, School of Biological Sciences, PMB 2000, ETTI, Emo State, Nigeria

The mechanism by which amino acids increase the cellular levels of orotic acid (OA) was investigated. Administration of glycine (2.5 mmoles/100 g) to rats resulted in a 100-fold increase in urinary OA excretion, which was inhibited by pretreatment with cycloheximide or actinomycin D. The induction of OA synthesis from NH₄Cl but not from carbamoylaspartate (CA) was inhibited by cycloheximide, indicating that the cycloheximide sensitive step was after the formation of ammonia and before the formation of CA. The glycine-stimulated OA synthesis was not inhibited by acivicin, a potent inhibitor of the cytosolic carbamoylphosphate (CP) synthetase, implicating the mitochondrial CP synthetase in supplying the CP for OA synthesis. Preliminary results indicated that cycloheximide did not inhibit glycine-induced urea synthesis to any significant extent. The results thus suggest that (i) the increased OA synthesis induced by glycine requires a transcription-translation dependent step and (ii) the regulatory step may be the transport of mitochondrial CP to cytosol and/or the synthesis of cytosolic CA. Attempts to determine whether increased exposure of urinary bladder to high concentrations of OA will influence bladder tumorigenesis revealed that chronic administration of glycine (2.5 mmoles/100 g, ip, daily, 5 days a week for 20 weeks) resulted in a 44% increased incidence of hyperplastic, preneoplastic, and neoplastic lesions. Some of these rats also exhibited stones in urinary bladders. The mechanism by which glycine induces tumorigenesis in the urinary bladder is currently being explored.

Toxicologic Pathology, Vol. 15, No. 2, 194-197 (1987)
DOI: 10.1177/019262338701500211


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