Collection of Czechoslovak Chemical Communications - digital archive 

Abstract

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.