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Orotic Aciduria Due to Arginine Deprivation: Changes in the Levels of Carbamoyl Phosphate and of Other Urea Cycle Intermediates in Mouse Liver¹

Instituto de Investigaciones Citológicas de la Caja de Ahorros de Valencia (Centro Asociado del CSIC), Amadeo de Saboya, 4. Valencia. 46010- Spain

The orotic aciduria induced in mammals by arginine deprivation is believed to result from accumulation of carbamoyl phosphate in liver, but this accumulation has never been demonstrated in vivo during arginine deprivation. There has been disagreement even on the basal levels of carbamoyl phosphate. In this report we show, using an improved assay, that the hepatic level of carbamoyl phosphate is very low (< 1.3 nmol/g) in the fasted mouse or after a meal containing a mixture of amino acids including arginine, and that it increases dramatically (up to 180 nmol/g liver) after a meal without arginine. We estimated a fast turnover for carbamoyl phosphate, and we found a marked correlation between liver carbamoyl phosphate and urinary orotate, and also between urinary orotate and intake of an arginine-free diet. These results support the hypothesis that accumulation of carbamoyl phosphate in liver mitochondria, its efflux from this organelle and its utilization by the cytosolic pyrimidine pathway cause the orotic aciduria of arginine deprivation. We assayed liver acetylglutamate (the activator of carbamoyl phosphate synthesis) and several intermediates of the urea cycle and found that low levels of ornithine partly explain the accumulation of carbamoyl phosphate during arginine deprivation. However, acetylglutamate and citrulline were increased, and the potential significance of these changes is discussed.

KEY WORDS: • carbamoyl phosphate • orotic aciduria • arginine deprivation • ornithine • mice

¹ Supported in part by grant no. 2648-83 from the Comisión Asesora de Investigación Científica y Técnica (CAICYT) and 89/0554 from the Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS). E. Alonso is a fellow of the FIS and V. Rubio is Investigador del CSIC and a member of the IIC-KUMC International Molecular Cytology Exchange Program.

² To whom reprint requests should be sent.

Manuscript received 28 September 1988. Revision accepted 12 April 1989.