beta-carboline analogues of MPP+ as environmental neurotoxins

Carbolines (pyrido-indoles) are prevalent tryptophan-derived heterocyclics in the diet and environment that have been linked since the late 1970's to carcinogenesis. Evidence from our and other laboratories suggests the possi bility that the most common pyrido-indole isomers, the beta -carbolines, al so might be "protoxicants" leading to neuronal damage and resultant idiopat hic parkinsonism in susceptible individuals. There is a close structural si milarity between the N-methylated cationic products of simple beta -carboli nes (e.g., norharman or harman) and the parkinsonian neurotoxin, MPTP, or s pecifically, its active cationic metabolite, MPP+. The N-methylated beta -c arbolinium species are formed in mammalian brain via one or possibly two en zymatic S-adenosylmethionine-dependent N-methylations. These chemical alter ations metabolically bioactivate the molecules, greatly increasing both the mitochondrial inhibitory activity and the in vitro and in vivo dopaminergi c toxicity of the beta -carboline nucleus. Furthermore, the second (indole nitrogen) methylating activity as well as the product (2,9-di-N-methylated) carbolinium cations appear to be elevated in parkinsonian brain. Matsubara 's studies (this volume) demonstrate nigrostriatal neurodegeneration and ne urobehavioral impairment in mice given precursors of the beta -carbolinium cations. In view of these findings, epidemiological studies on the possible relationship between environmental carboline alkaloid exposure and idiopat hic parkinsonism could be revealing.