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

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Title:New Selective Inhibitors of Cytochrome P450 2B4 and an Activator of Cytochrome P450 3A6 in Rabbit Liver Microsomes
Creators:
Bořek-Dohalská, Lucie
Hodek, Petr
Stiborová, Marie
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 65, 1, pp. 122-132
Uncontrolled Keywords:Inhibitors, Diamantane, Oxidations, Activators, CYP2B4, Adamantane, 3-Isopropenyl-3-methyldiamantane, CYP3A6, 2-Isopropenyl-2-methyladamantane, Cytochrome P450

Abstract

We investigated interactions of adamantane, diamantane and their two substituted derivatives, 2-isopropenyl-2-methyladamantane (2-PMADA, <strong>1</strong>) and 3-isopropenyl-3-methyldiamantane (3-PMDIA, <strong>2</strong>), 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. <strong>1</strong> and <strong>2</strong> are compounds having higher affinities to these CYP isoforms than adamantane and diamantane. All compounds inhibit CYP2B4 specific enzyme activity (the 7-pentoxyresorufin <i>O</i>-depentylase activity). The 50% inhibition of CYP2B4 was due to 3.82, 0.61, 0.66 and 0.37 μM adamantane, diamantane, <strong>1</strong> and <strong>2</strong>, respectively. The products formed during the CYP2B4-mediated metabolism of studied substances are less effective inhibitors than parent compounds. An opposite effect of <strong>1</strong> on CYP3A6 was determined. The specific enzyme activity of CYP3A6 increased to 138% of control when <strong>1</strong> 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. <p>

Title:New Selective Inhibitors of Cytochrome P450 2B4 and an Activator of Cytochrome P450 3A6 in Rabbit Liver Microsomes
Creators:
Bořek-Dohalská, Lucie
Hodek, Petr
Stiborová, Marie
Uncontrolled Keywords:Inhibitors, Diamantane, Oxidations, Activators, CYP2B4, Adamantane, 3-Isopropenyl-3-methyldiamantane, CYP3A6, 2-Isopropenyl-2-methyladamantane, Cytochrome P450
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:65
Number:1
Page Range:pp. 122-132
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc20000122UNSPECIFIED
ID Code:1629
Item Type:Article
Deposited On:06 Feb 2009 17:11
Last Modified:06 Feb 2009 16:11

Citation

Bořek-Dohalská, Lucie; Hodek, Petr; Stiborová, Marie (2000) New Selective Inhibitors of Cytochrome P450 2B4 and an Activator of Cytochrome P450 3A6 in Rabbit Liver Microsomes. Collection of Czechoslovak Chemical Communications, 65 (1). pp. 122-132. ISSN 0010-0765

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