title: Interaction of selected platinum(II) complexes containing roscovitine-based CDK inhibitors as ligands with human liver microsomal cytochrome P450.
abstract: BACKGROUND
  We studied the interaction of oxaliplatin derivatives involving cytotoxic adenine-based cyclin-dependent kinase inhibitors, with human liver microsomal cytochrome P450.
  
  
  RESULTS
  The activities of 9 human liver microsomal CYP forms (CYPs 1A2, 7-ethoxyresorufin O-deethylation; 2A6, coumarin 7-hydroxylation; 2B6, 7-ethoxy-4-(trifluoromethyl) coumarin O-deethylation; 2C8, luciferin-6´ methyl ether demethylation; 2C9, diclofenac 4´-hydroxylation, 6´-deoxyluciferin hydroxylation; 2C19, (S)-mephenytoin 4´-hydroxylation; 2D6, bufuralol 1´-hydroxylation, 2E1, chlorzoxazone 6-hydroxylation; 3A4, testosterone 6β-hydroxylation, luciferin-6´ benzyl ether debenzylation) were tested using HPLC, fluorescence and luminescence product detection. At 100 µM platinum(II) oxalato complex concentration, CYP inhibition was in general 25%-50%, except for the CYP3A4 form which showed roughly twice the inhibition (72%-95%). At low complex concentration (10 µM), the difference in inhibition of CYP3A4 and other forms was even more pronounced. Dixon and Lineweaver-Burk plots indicated a partially noncompetitive mechanism of CYP3A4 inhibition.
  
  
  CONCLUSIONS
  The tested complexes significantly inhibit human liver microsomal CYP3A4 activity even at clinically relevant concentrations. This could be a serious drawback for the use of these compounds in clinical practice.
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.|Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc.
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Masek
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Inorganic Chemistry, Faculty of Science, Palacky University Olomouc.
authors.forename: Pavel
authors.initials: P
authors.lastname: Starha
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.|Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc.
authors.forename: Monika
authors.initials: M
authors.lastname: Harvanova
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.|Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc.
authors.forename: Martina
authors.initials: M
authors.lastname: Michalova
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Analytical Chemistry, Faculty of Science, Palacky University Olomouc.
authors.forename: David
authors.initials: D
authors.lastname: Milde
authors.affiliation: Regional Centre of Advanced Technologies and Materials, Department of Inorganic Chemistry, Faculty of Science, Palacky University Olomouc.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Travnicek
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University Olomouc.
authors.forename: Eva
authors.initials: E
authors.lastname: Anzenbacherova
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D017671:Platinum Compounds / Q000378:metabolism*
chemical_list: D008024:Ligands; D017671:Platinum Compounds; D051544:Cytochrome P-450 CYP3A
keywords: CDK inhibition; cytochrome P450; platinum(II) complexes; roscovitine derivatives