L. Borek-dohalska et al., New selective inhibitors of cytochrome P4502B4 and an activator of cytochrome P450 3A6 in rabbit liver microsomes, COLL CZECH, 65(1), 2000, pp. 122-132
Citations number
37
Categorie Soggetti
Chemistry
Journal title
COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS
We investigated interactions of adamantane, diamantane and their two substi
tuted derivatives, 2-isopropenyl-2-methyladamantane (2-PMADA, 1) and 3 isop
ropenyl-3-methyldiamantane (3-PMDIA, 2), with various isoforms of rabbit cy
tochrome 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 isofor
ms than adamantane and diamantane. All compounds inhibit CYP2B4 specific en
zyme activity (the 7-pentoxyresorufin O-depentylase activity). The 50% inhi
bition of CYP2B4 was due to 3.82, 0.61, 0.66 and 0.37 mu M adamantane, diam
antane, 1 and 2, respectively. The products formed during the CYP2B4-mediat
ed metabolism of studied substances are less effective inhibitors than pare
nt compounds. An opposite effect of 1 on CYP3A6 was determined. The specifi
c enzyme activity of CYP3A6 increased to 138% of control when 1 was used in
the presence of 40 mu M erythromycin as a substrate. Here, we report the f
inding of a new activator of CYP3A6 having the structure quite different fr
om that of CYP3A6 activators known to date.