Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003405-02
Application #
3207891
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1984-07-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Rollema, H; Alexander, G M; Grothusen, J R et al. (1989) Comparison of the effects of intracerebrally administered MPP+ (1-methyl-4-phenylpyridinium) in three species: microdialysis of dopamine and metabolites in mouse, rat and monkey striatum. Neurosci Lett 106:275-81
Hoag, M K; Schmidt-Peetz, M; Lampen, P et al. (1988) Metabolic studies on phencyclidine: characterization of a phencyclidine iminium ion metabolite. Chem Res Toxicol 1:128-31
Trevor, A J; Castagnoli, N; Singer, T P (1988) The formation of reactive intermediates in the MAO-catalyzed oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicology 49:513-9
Di Monte, D; Shinka, T; Sandy, M S et al. (1988) Quantitative analysis of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine metabolism in isolated rat hepatocytes. Drug Metab Dispos 16:250-5
Singer, T P; Ramsay, R R; McKeown, K et al. (1988) Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicology 49:17-23
Rollema, H; Booth, R G; Castagnoli Jr, N (1988) In vivo dopaminergic neurotoxicity of the 2-beta-methylcarbolinium ion, a potential endogenous MPP+ analog. Eur J Pharmacol 153:131-4
Singer, T P; Castagnoli Jr, N; Ramsay, R R et al. (1987) Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 49:1-8
Trevor, A J; Singer, T P; Ramsay, R R et al. (1987) Processing of MPTP by monoamine oxidases: implications for molecular toxicology. J Neural Transm Suppl 23:73-89
Trevor, A J; Castagnoli Jr, N; Caldera, P et al. (1987) Bioactivation of MPTP: reactive metabolites and possible biochemical sequelae. Life Sci 40:713-9
Di Monte, D; Ekstrom, G; Shinka, T et al. (1987) Role of 1-methyl-4-phenylpyridinium ion formation and accumulation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity to isolated hepatocytes. Chem Biol Interact 62:105-16

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