Summary
Tritium labelled 1-carboxy-tetrahydroharman was identified in rat brain following i. c. v.-injection of [3H]tryptamine and pyruvic acid. The animals had been treated with the MAO inhibitor pargyline (40 mg/kg) 30 min before i. c. v. injection. Under these conditions, only trace amounts of [3H]indole acetic acid could be detected in the brain. The formation of 1-CTHH was time-dependent. Five minutes following the i. c. v. injection, approximately 0.45% of the administered tryptamine was converted into 1-CTHH and 23% were still unchanged. The amount of the radioactive 1-CTHH increased slightly within 1 h (0.8%; [3H] tryptamine: 6%). Pretreatment of the rats with high doses of pargyline (75 mg/kg; 90 min before i. c. v. injection) prevented the formation of both [3H]1-CTHH and [3H]indole acetic acid (IAA) suggesting that high doses of pargyline inhibit the formation of 1-CTHH. As control for a possible non-enzymatic formation of 1-CTHH, [3H]tryptamine and various concentrations of pyruvic acid were incubated in phosphate buffer at pH 7.4. 1-CTHH was not detected under these conditions. However, the formation of 1-CTHH was observed at high pyruvic acid concentrations (final concentration = 100 mM) and low pH values (< pH4). To support the assumption that the observed condensation of both precursors to 1-CTHH occurred intracellularly, the metabolism of tryptamine was studied. Two minutes after i. c. v. injection of [3H]tryptamine approximately 4% of the injected dose remained unchanged and 10% were metabolized to [3H]IAA. These findings suggest a rapid disappearance of [3H]tryptamine from the cerebrospinal fluid as well as a rapid penetration into the cerebral tissue.
The identification of the 1-CTHH formed after in vivo administration of both precursors was carried out by thin layer chromatography in various solvent systems, methylation yielding the methyl ester derivative and in vitro decarboxylation to harmalan with rat liver homogenate and PLP as co-enzyme.
The present results suggest an alternative pathway for the biosynthesis of β-carbolines in rats.
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Abbreviations
- BC:
-
β-carboline
- 1-CTHH:
-
1-carboxy-tetrahydroharman, 1,2,3,4-tetrahydro-1-methyl-β-carboline-1-carbolic acid
- 1H-NMR:
-
nuclear magnetic resonance
- IAA:
-
indole acetic acid
- i.c.v.:
-
intracerebroventricular
- i.p.:
-
intraperitoneal
- MAO:
-
monoamine oxidase
- m. p.:
-
melting points
- MS:
-
mass spectroscopy
- p.i.:
-
post injectionem
- PLP:
-
pyridoxal-5-phosphate
- THH:
-
tetrahydroharman
- TLC:
-
thin layer chromatography
- TMS:
-
tetramethylsilane
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This study was supported by the Deutsche Forschungsgemeinschaft
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Susilo, R., Rommelspacher, H. Formation of a β-carboline (1,2,3,4-tetrahydro-l-methyl-β-carboline-1-carboxylic acid) following intracerebroventricular injection of tryptamine and pyruvic acid. Naunyn-Schmiedeberg's Arch Pharmacol 335, 70–76 (1987). https://doi.org/10.1007/BF00165039
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DOI: https://doi.org/10.1007/BF00165039