BETA-CARBOLINES - METABOLISM AND NEUROTOXICITY

Hydrophobic beta-carbolines (such as norharman or harman) derived from tryptophan-containing environmental sources and, possibly, from in vi vo biosynthesis are converted by brain enzymes to cationic cytotoxican ts that structurally resemble MPP(+). The carbolinium cytotoxicants ha ve been detected and measured in human brain and spinal fluid. We sugg est that, over time, bioactivated beta-carbolines and other protoxican t heterocyclics may be crucial in the excessive nigrostriatal degenera tion which distinguishes Parkinson's disease. The critical overall bio activation step is considered to be sequential methylation within brai n to form 2,9-di-N-methylated carbolinium cations which,like MPP(+), i nhibit mitochondrial respiration and cause neuronal death. However, ot her toxic mechanisms for the cations are possible. In addition, neurot oxicity data with neuronal cultures indicate that hydroxylation and O- methylation of the indole moiety could be an unappreciated facet of en dogenous beta-carboline bioactivation pathways as well.