Para-chloroamphetamine (PCA) selectively destroys serotonergic neurons in the central nervous system for up to 4 months following administration to laboratory animals. The long-term toxicity involves reduction in tryptophane hydroxylase activity (reduced amounts of enzyme) and irreversible cellular destructon. N-methyl-4-phenyl-tetra-hydropyridine (MPTP) is found in several street drugs, and following ingestion by humans, leads to long-term neurotoxicity characterized by a Parkinson-like syndrome and destruction of nigrostriatal cells. Para-chlorophenylalanine (PCPA) is used in the treatment of carcinoid syndrome and causes depression and other dose-limiting neurotoxic effects in humans. PCPA is a irreversible long-term inhibitor of tryptophane hydroxylase in animals. There is evidence to suggest that the long-term neurotoxicity of the model compound PCA is mediated by a metabolite. As part of the initial award, we documented that PCA is converted to alkylating metabolites (measured by covalent binding to microsomal proteins) by rat liver microsomal monooxygenases, and more importantly, by rat brain microsomal monooxygenases. We are studying metabolic pathway responsible for activation of PCA, and correlating stereochemical aspects of PCA metabolism to known stereochemical aspects of PCA neurotoxicity. The long-term objectives of the continuation are to document metabolic activation of PCA in vivo and further characterize the metabolic activation, and to determine if the selective irreversible and long-term neurotoxic affects of MPTP and PCPA are mediated by metabolic activation of these agents.
Specific aims are 1) to continue in vivo and in vitro metabolic activation studies with PCA to determine activation of PCA in vivo and identify reactive metabolites, 2) to determine if MPTP and PCPA are metabolically activated by animal liver and brain microsomal preparations as measured by covalent binding to tissue macromolecules, and 3) to elucidate metabolic pathways of MPTP and PCPA associated with metabolic activation. Methods include metabolic activation studies in which radiolabeled substrates are incubated with microsomal preparations and enzymatic-dependent covalent binding to proteins determined, and identification of enzymes and metabolites responsible for activation. The significance of these studies will be to determine if metabolic activation may be a general mechanism of neurotoxicity for agents which exhibit neurotoxicity in humans, and to better characterize metabolic pathways which may lead to neurotoxic events.
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