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Ornithine aminotransferase activity, tissue ornithine concentrations and polyamine metabolism
N Seiler1, G Daune, F N Bolkenius
1Merrell Dow Research Institute, Strasbourg, France.
Abstract:
1. Inactivation of L-ornithine:2-oxoacid aminotransferase (OAT) by 5-fluoromethylornithine (5FMOrn), a specific inactivator of OAT, causes a great elevation of tissue ornithine (Orn) concentrations. 2. Inhibition of L-ornithine decarboxylase (ODC) by 2-difluoromethylornithine (DFMO) had no effect on Orn concentrations. 3. The combined administration of 5FMOrn and DFMO produced a 2- to 3-fold greater enhancement of tissue Orn concentrations than treatment with 5FMOrn alone. 4. The increase of tissue Orn concentrations had a long-lasting enhancing effect on polyamine metabolism. 5. In the brain this could be demonstrated by the elevation of putrescine and spermidine concentrations and the increase of spermidine turnover rate. 6. In visceral organs polyamine concentrations were not elevated because polyamines can be eliminated by transport. 7. In line with this notion is the fact that urinary polyamine excretion was increased for several days, even after a single dose of 5FMOrn. 8. Inhibitors of 4-aminobutyric acid:2-oxoglutarate aminotransferase which are also inactivators of OAT had the same effect on polyamine excretion as 5FMOrn.
Insights
Inhibiting L-ornithine:2-oxoacid aminotransferase (OAT) with 5-fluoromethylornithine (5FMOrn) significantly elevates ornithine (Orn) levels, impacting polyamine metabolism. Combined with ODC inhibition, this effect is amplified, leading to increased polyamine excretion.
Area of Science:
- Biochemistry
- Pharmacology
- Metabolic pathways
Background:
- L-ornithine:2-oxoacid aminotransferase (OAT) plays a role in ornithine metabolism.
- L-ornithine decarboxylase (ODC) is involved in polyamine synthesis.
- Understanding ornithine and polyamine regulation is crucial for metabolic research.
Purpose of the Study:
- To investigate the effects of OAT inactivation on ornithine concentrations and polyamine metabolism.
- To determine the impact of combined OAT and ODC inhibition on ornithine levels.
- To explore the relationship between tissue ornithine and polyamine excretion.
Main Methods:
- Administration of 5-fluoromethylornithine (5FMOrn), a specific OAT inactivator.
- Administration of 2-difluoromethylornithine (DFMO), an ODC inhibitor.
- Measurement of tissue and urinary ornithine and polyamine concentrations.
Main Results:
- 5FMOrn treatment caused significant elevation of tissue ornithine concentrations.
- Combined 5FMOrn and DFMO administration resulted in a 2- to 3-fold greater increase in tissue ornithine compared to 5FMOrn alone.
- Elevated ornithine levels enhanced polyamine metabolism, evidenced by increased putrescine and spermidine in the brain and increased urinary polyamine excretion.
Conclusions:
- Inactivation of OAT is a potent method for increasing tissue ornithine concentrations.
- Combined inhibition of OAT and ODC synergistically elevates ornithine levels.
- Increased ornithine concentrations have a long-lasting effect on polyamine metabolism and excretion.