Abstract
Metabolism studies were conducted in order to investigate the reasons for the in vivo lack of activity of (-)-rhazinilam 1, an original poison of the mitotic spindle. Bioconversion by Beauveria bassiana strains, rat and human liver microsomes allowed the identification of metabolites 2, 3, and 4 oxidized in positions 3 and 5 of rhazinilam. Further experiments indicated that CYP2B6 was the main CYP responsible for the oxidation of 1 by human liver microsomes. All isolated metabolites were markedly less active than rhazinilam in vitro, which might explain its in vivo inactivity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / metabolism*
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Alkaloids / pharmacology
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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Aryl Hydrocarbon Hydroxylases / metabolism
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Biotransformation
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Cordyceps / drug effects*
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Cordyceps / growth & development
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Crystallography, X-Ray
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Cytochrome P-450 CYP2B6
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Gas Chromatography-Mass Spectrometry
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Humans
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Indolizines / metabolism
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Indolizines / pharmacology
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Lactams / metabolism
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Lactams / pharmacology
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Microsomes, Liver / enzymology
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Oxidation-Reduction
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Oxidoreductases, N-Demethylating / metabolism
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Rats
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Spindle Apparatus / metabolism
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Time Factors
Substances
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Alkaloids
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Antineoplastic Agents
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Indolizines
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Lactams
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rhazinilam
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Aryl Hydrocarbon Hydroxylases
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CYP2B6 protein, human
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Cytochrome P-450 CYP2B6
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Oxidoreductases, N-Demethylating