Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation

Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis–Menten K m and V max for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 μM and 1.48 nmol/min/n...

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Published in:European journal of medicinal chemistry 2008-06, Vol.43 (6), p.1171-1179
Main Authors: Julsing, Mattijs K., Vasilev, Nikolay P., Schneidman-Duhovny, Dina, Muntendam, Remco, Woerdenbag, Herman J., Quax, Wim J., Wolfson, Haim J., Ionkova, Iliana, Kayser, Oliver
Format: Article
Language:English
Subjects:
Algorithms
Automated docking
Biological and medical sciences
Chromatography, High Pressure Liquid
Cytochrome P-450 CYP3A - metabolism
Cytochrome P450 3A4 (EC 1.14.14.1)
Drug metabolism
Epipodophyllotoxin
General pharmacology
Humans
Lignans
Medical sciences
Models, Molecular
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Podophyllotoxin - analogs & derivatives
Podophyllotoxin - metabolism
Recombinant Proteins - metabolism
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Summary:Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis–Menten K m and V max for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 μM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the β-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans. [Display omitted]
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2007.09.005