Summary
Mice with the X-chromosomal sparse-fur (spf) mutation are an animal model of some hereditary deficiencies of ornithine carbamoyltransferase (OCT) in man. Orotic aciduria and hyperammonaemia are the most conspicuous metabolic changes in these diseases. Selective inactivation of ornithine aminotransferase (OAT) by 5-fluoromethylornithine raises endogenous ornithine concentrations so that citrulline formation is effectively catalysed by the aberrant OCT, in spite of its low affinity for ornithine. As a consequence, blood and tissue ammonia concentrations and orotic acid excretion are reduced near to normal values, and the abnormal amino acid patterns in blood, brain and liver are normalized. Selective inactivation of OAT seems a promising therapeutic approach in some hereditary OCT deficiencies, and a tool that may allow us to clarify the role of ammonia and orotic acid in the development of nanism and abnormal behaviour in spf mutant mice.
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Bachmann C, Colombo JP (1980) Diagnostic value of orotic acid excretion in heritable disorders of the urea cycle and in hyperammonemia due to organic acidurias.Eur J Pediatr 134: 109–113.
Briand P, François B, Rabier D, Cathelineau L (1982) Ornithine transcarbamylase deficiencies in human males; kinetic and immunochemical classification.Biochim Biophys Acta 704: 100–106.
Ceriotti G (1974) Ornithine carbamoyltransferase. In Bergmeyer HK, ed.Methods in Enzymatic Analysis, vol. 2. Weinheim: Verlag Chemie, 691–698.
Daune G, Gerhart F, Seiler N (1988) 5-Fluoromethylornithine, an irreversible and specific inhibitor ofl-ornithine: 2-oxo-acid aminotransferase.Biochem J 253: 481–488.
Daune-Anglard G, Bonaventure N, Seiler N (1993) Some biochemical and pathophysiological aspects of long-term elevation of brain ornithine concentrations.Pharmacol Toxicol 73: 29–34.
DeMars R, LeVan SL, Trend BL, Russell LB (1976) Abnormal ornithine carbamoyltransferase in mice having the sparse-fur mutation.Proc Natl Acad Sci USA 73: 1693–1697.
Levin R, Dobbs RH, Burgess A, Palmer T (1969) Hyperammonemia. A variant type of deficiency of liver ornithine transcarbamylase.Arch Dis Child 44: 162–169.
Loken F (1954) Creatinine determination.Scand J Clin Lab Invest 6: 325–332.
Nelson J, Qureshi IA, Vasudevan S, Sarma DSR (1993) The effect of various inhibitors on the regulation of orotic acid excretion in sparse-fur mutant mice (spf/Y) deficient in ornithine transcarbamylase.Chem Biol Interact 89: 35–47.
Rabier D, Benoit A, Petit F et al (1989) Ornithine carbamoyltransferase deficiency. A new variant with subnormal enzyme activity.Clin Chim Acta 186: 25–30.
Seiler N (1981) Polyamine metabolism and function in brain.Neurochem Int 3: 95–110.
Seiler N, Knödgen B (1985) Determination of amino acids by separation of their ion pairs with dodecyl sulphate.J Chromatogr 341: 11–21.
Seiler N, Spraggs H, Daune G (1987) Interrelationships between ornithine, glutamate and GABA. I. Feed-back inhibition of ornithine aminotransferase by elevated brain GABA levels.Neurochem Int 10: 391–397.
Seiler N, Sarhan S, Grauffel C, Jones R, Knödgen B, Moulinoux JP (1990) Endogenous and exogenous polyamines in support of tumor growth.Cancer Res 50: 5077–5083.
Seiler N, Sarhan S, Knoedgen B, Hornsperger JM, Sablone M (1993) Enhanced endogenous ornithine concentrations protect against tonic seizures and coma in acute ammonia intoxication.Pharmacol Toxicol 72: 116–123.
Seiler N, Grauffel C, Therrien G, Sarhan S, Knoedgen B (1994) Determination of orotic acid in urine.J Chromatogr B 653: 87–91.
Soubrie P, Thiebot MH, Simon P, Boissier JR (1977) Effet des benzodiazepines sur les phénomènes d'inhibition qui contrôlent les comportements exploratoires et le recueil de l'information chez le rat.J Pharmacol (Paris) 3: 393–403.
Therrien G, Sarhan S, Knödgen B, Butterworth RF, Seiler N (1994) Effects of ornithine aminotransferase inactivation by 5-fluoromethylornithine in rats following portocaval anastomosis.Metab Brain Dis, in press.
Weischer ML (1976) Eine einfache Versuchsanordnung zur quantitativen Beurteilung von Motilität und Neugierverhalten bei Mäusen.Psychopharmacology 50: 275–279.
Zieve L (1986) Conditional deficiencies of ornithine or argine.J Am Coll Nutr 5: 167–176.
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Seiler, N., Grauffel, C., Daune-Anglard, G. et al. Decreased hyperammonaemia and orotic aciduria due to inactivation of ornithine aminotransferase in mice with a hereditary abnormal ornithine carbamoyltransferase. J Inherit Metab Dis 17, 691–703 (1994). https://doi.org/10.1007/BF00712011
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DOI: https://doi.org/10.1007/BF00712011