Interactions of olomoucine II with human liver microsomal cytochromes P450.
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.
Siller
Michal
M
Palacky University at Olomouc, Faculty of Medicine and Dentistry, Department of Pharmacology, Olomouc, Czech Republic. michal.siller@seznam.cz
Anzenbacher
Pavel
P
Anzenbacherova
Eva
E
Dolezal
Karel
K
Popa
Igor
I
Strnad
Miroslav
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000494:pharmacology*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065702:Cytochrome P-450 CYP2B6; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating; D011687:Purines / Q000494:pharmacology*; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D011687:Purines; C475587:olomoucine II; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating