Collect. Czech. Chem. Commun. 2000, 65, 122-132

New Selective Inhibitors of Cytochrome P450 2B4 and an Activator of Cytochrome P450 3A6 in Rabbit Liver Microsomes

Lucie Bořek-Dohalská*, Petr Hodek and Marie Stiborová

Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030, 128 43 Prague 2, Czech Republic


We investigated interactions of adamantane, diamantane and their two substituted derivatives, 2-isopropenyl-2-methyladamantane (2-PMADA, 1) and 3-isopropenyl-3-methyldiamantane (3-PMDIA, 2), with various isoforms of rabbit cytochrome P450 (CYP). The data of spectroscopic experiments showed that all the substances are bound to the substrate binding site of rabbit CYP2B4 and CYP3A6. 1 and 2 are compounds having higher affinities to these CYP isoforms than adamantane and diamantane. All compounds inhibit CYP2B4 specific enzyme activity (the 7-pentoxyresorufin O-depentylase activity). The 50% inhibition of CYP2B4 was due to 3.82, 0.61, 0.66 and 0.37 μM adamantane, diamantane, 1 and 2, respectively. The products formed during the CYP2B4-mediated metabolism of studied substances are less effective inhibitors than parent compounds. An opposite effect of 1 on CYP3A6 was determined. The specific enzyme activity of CYP3A6 increased to 138% of control when 1 was used in the presence of 40 μM erythromycin as a substrate. Here, we report the finding of a new activator of CYP3A6 having the structure quite different from that of CYP3A6 activators known to date.

Keywords: Cytochrome P450; CYP2B4; CYP3A6; Inhibitors; Activators; Adamantane; Diamantane; 2-Isopropenyl-2-methyladamantane; 3-Isopropenyl-3-methyldiamantane; Oxidations.

References: 37 live references.