METABOLITES FROM TERTIARY AMINES--PHENCYCLIDINE

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Investigations are proposed to assess the biomedical significance of iminium intermediates formed via cytochrome P-450 mediated metabolism of tertiary amines. Phencyclidine will be used as a model compound to examine the reactivity of these electrophilic ions towards biomacromolecules. Biochemical mechanisms underlying metabolism-dependent inhibition of cytochrome P-450 enzymic activities by phencyclidine will be investigated using hepatic microsomal preparations in vitro and reconstituted, purified cytochrome P-450 systems. Iminium species will be synthesized, their reactivity towards model compounds will be studied, and the structure of adducts formed will be characterized by mass spectral methods. The extent to which the formation of iminium intermediates is specific to tissues and species will be determined by use of 14CN- trappping methods. Documentation of the formation of iminium intermediates and their reactions with biomacromolecules should provide insight into the molecular mechanisms associated with the toxic actions of tertiary amines, many of which are useful therapeutic agents.