Abstract
Olomoucine II is a cyclin-dependent kinase inhibitor and a potential antineoplastic agent because it can arrest animal cell cycles. This study examines its interactions with human liver microsomal cytochrome P450 (P450) enzymes. Spectroscopic and high-performance liquid chromatography (HPLC) methods were used to estimate the degree of olomoucine II-mediated inhibition of enzymatic activities of eight drug-metabolizing P450s in vitro. In addition, mass spectrometry coupled with HPLC was used to identify an olomoucine II metabolite (2,5-dihydroxyroscovitine) formed in the reaction mixtures, and CYP3A4 was found to be responsible for the hydroxylation of the N(6)-benzyl ring at position 5, leading to this compound. Olomoucine II significantly inhibited the enzymatic activities of CYP1A2, CYP2C9, and (to a lesser degree) CYP3A4. The results indicate that use of olomoucine II as a drug could affect the activities of CYP3A4, CYP1A2, and CYP2C9 in vivo. Hence, the clinical relevance of these interactions should be carefully evaluated.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
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Chromatography, High Pressure Liquid
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Cyclin-Dependent Kinase Inhibitor Proteins / pharmacology*
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Cytochrome P-450 CYP1A2 Inhibitors
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Cytochrome P-450 CYP2B6
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Cytochrome P-450 CYP2C9
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors*
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Cytochrome P-450 Enzyme Inhibitors
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Drug Interactions
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Humans
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Liver / cytology
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Liver / enzymology
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Microsomes, Liver / drug effects*
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Microsomes, Liver / enzymology
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Oxidoreductases, N-Demethylating
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Purines / pharmacology*
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Substrate Specificity
Substances
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Antineoplastic Agents
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Cyclin-Dependent Kinase Inhibitor Proteins
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Cytochrome P-450 CYP1A2 Inhibitors
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Cytochrome P-450 CYP3A Inhibitors
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Cytochrome P-450 Enzyme Inhibitors
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Purines
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olomoucine II
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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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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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Oxidoreductases, N-Demethylating