Toxicity and metabolism of the chloral-derived mammalian alkaloid 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) in PC12 cells.

Abstract

Chloral-derived beta-carbolines, which are structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 5), are discussed to contribute to neuronal cell death in idiopathic Parkinson's disease. The cytotoxicity of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo, 4) to neuronal-like clonal pheochromocytoma PC12 cells was examined by the determination of lactate dehydrogenase (LDH) release. After incubation for 48 h, 4 showed a strong dose-dependent cytotoxic activity towards PC12 cells with an ED50 value of 230 microM. In PC12 cells reductive dehalogenation of 4 was observed giving rise to the formation of 1-dichloromethyl-1,2,3,4-tetrahydro-beta-carboline (6) as a main TaClo metabolite exhibiting a cytotoxic potential comparable to that of TaClo. An X-ray structure analysis, performed for the trifluoroacetyl derivative of 6, revealed the N-substituent of such a highly chlorinated agent to be dramatically pushed out of the beta-carboline ring 'plane' due to the high steric demand of the huge dichloromethyl group at C(1).

• Authors: Gerhard Bringmann, Doris Feineis, Miriam Münchbach, Ralf God, Karl Peters, Eva-Maria Peters, Rainald Mössner, Klaus-Peter Lesch
• Journal: Zeitschrift fur Naturforschung. C, Journal of biosciences (Z Naturforsch C J Biosci) 2006 Jul-Aug Vol. 61 Issue 7-8 Pg. 601-10 ISSN: 0939-5075 [Print] Germany
• PMID: 16989324 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbolines
• 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline
• L-Lactate Dehydrogenase

Topics

• Animals
• Carbolines (chemistry, metabolism, toxicity)
• Cell Death
• Cell Survival (drug effects)
• L-Lactate Dehydrogenase (analysis)
• Models, Molecular
• Molecular Conformation
• PC12 Cells
• Pheochromocytoma
• Rats