beta-Carbolines: Metabolism and neurotoxicity

Hydrophobic beta-carbolines (such as norharman or harman) derived from tryptophan-containing environmental sources and, possibly, from in vivo biosynthesis are converted by brain enzymes to cationic cytotoxicants that structurally resemble MPP(+). The carbolinium cytotoxicants have been detected and measured in human brain and spinal fluid. We suggest that, over time, bioactivated beta-carbolines and other protoxicant heterocyclics may be crucial in the excessive nigrostriatal degeneration which distinguishes Parkinson's disease. The critical overall bioactivation step is considered to be sequential methylation within brain to form 2,9-di-N-methylated carbolinium cations which,like MPP(+), inhibit mitochondrial respiration and cause neuronal death. However, other toxic mechanisms for the cations are possible. In addition, neurotoxicity data with neuronal cultures indicate that hydroxylation and O-methylation of the indole moiety could be an unappreciated facet of endogenous beta-carboline bioactivation pathways as well.