Metabolism of the Catharanthus Alkaloids: from Streptomyces griseus to Monoamine Oxidase B

More than three decades after their discovery and implementation in medicine, essentially nothing is known about the metabolism or the implications of metabolism in mechanism of action or toxicity of the Catharanthus alkaloids. The frustrating paucity of information about pathways of metabolism has...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 1992-03, Vol.55 (3), p.269-284
Main Authors: Rosazza, John P. N, Duffel, Michael W, El-Marakby, Sayed, Ahn, Sung Ho
Format: Article
Language:English
Subjects:
AGENTES ANTINEOPLASTICOS
ALCALOIDE
ALCALOIDES
ALKALOIDS
Animals
ANTINEOPLASTIC AGENTS
APOCYNACEAE
Biological and medical sciences
DRUG TOXICITY
DRUGS
FARMACOLOGIA
General pharmacology
Humans
Medical sciences
MEDICAMENT
MEDICAMENT CYTOSTATIQUE
MEDICAMENTOS
METABOLISM
METABOLISME
METABOLISMO
Monoamine Oxidase - metabolism
Monoamine Oxidase Inhibitors - pharmacology
PHARMACODYNAMICS
Pharmacognosy. Homeopathy. Health food
PHARMACOLOGIE
PHARMACOLOGY
Pharmacology. Drug treatments
TOXICIDAD
TOXICITE
TOXICITY
Vinca Alkaloids - metabolism
Vinca Alkaloids - pharmacology
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Summary:More than three decades after their discovery and implementation in medicine, essentially nothing is known about the metabolism or the implications of metabolism in mechanism of action or toxicity of the Catharanthus alkaloids. The frustrating paucity of information about pathways of metabolism has limited a major source of structure-activity relationship information and has blocked a critical avenue necessary for the logical development of new and more useful Catharanthus alkaloids. Microbial transformations, peroxidases, copper oxidases, mouse and rat cytochrome P-450 systems, and mouse brain and bovine liver monoamine oxidase (MAO) preparations have been explored in the study of Catharanthus alkaloid metabolism. In this report, we present results which have clarified the involvement of enzymatic and chemically catalyzed one-electron oxidations that yield nitrogen-centered cation radicals, iminium, and carbinolamine intermediates, all of which explain how new carbon-carbon and carbon-oxygen bonds form, or break and rearrange. The dimeric Catharanthus alkaloids are recalcitrant to oxidations catalyzed by monoamine oxidases and to both normal and induced P-450 rat microsomal preparations. However, the Catharanthus alkaloids appear to be selective reversible inhibitors of MAO-B. Chemical and biochemical aspects of the metabolic transformations of dimeric Catharanthus alkaloids are reviewed together with the implications of our findings.
ISSN:0163-3864
1520-6025
DOI:10.1021/np50081a001