Decreased hyperammonaemia and orotic aciduria due to inactivation of ornithine aminotransferase in mice with a hereditary abnormal ornithine carbamoyltransferase.

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.

Endogenous ornithine in search for CNS functions and therapeutic applications.

The vertebrate brain has the machinery to transport arginine and ornithine, and to form within nerve endings from these amino acids glutamate and GABA, the major excitatory and inhibitory neurotransmitters. Ornithine aminotransferase is a key enzyme of the Arg-->Orn-->Glu-->GABA pathway; the physiological significance of this pathway is still unclear. With 5-fluoromethylornithine, a selective inactivator of ornithine aminotransferase, a tool is in our hands that allows us to study biochemical and behavioral consequences of elevated tissue ornithine concentrations.

Some biochemical and pathophysiological aspects of long-term elevation of brain ornithine concentrations.

Mice and chicken were given 5-fluoromethylornithine (5FMOrn), a selective inactivator of ornithine aminotransferase (OAT) over extended periods of time. This treatment allowed us to maintain elevated concentrations of ornithine in all tissues. Since gyrate atrophy, an autosomal recessive human disease, is characterized by the absence of OAT, special emphasis was put on the study of the visual system.