title: New selective inhibitors of cytochromes P450 2B and their application to antimutagenesis of tamoxifen.
abstract: 2-Isopropenyl-2-methyladamantane (2-PMADA) and 3-isopropenyl-3-methyldiamantane (3-PMDIA) showed potent and selective inhibition of cytochrome P450 (CYP) 2B6-mediated reactions with K(i) values of 5.27 and 2.17 microM, respectively. No effect on activities of other human CYP was found even at concentrations 100-fold higher than those inhibiting CYP2B6. These results indicate that 2-PMADA and 3-PMDIA belong among the most potent CYP2B6-selective inhibitors discovered to date. Both compounds also inhibited reactions catalyzed by CYP2B2 and CYP2B4 with K(i) values ranging between 0.23 and 2 microM. They are competitive inhibitors of all CYP2B. The activation of the anticancer drug tamoxifen by human and rabbit microsomes generating tamoxifen-DNA adducts, which are responsible for carcinogenic side effects of this drug, was strongly inhibited by both compounds. 2-PMADA and 3-PMDIA are very potent for inhibition of formation of these DNA adducts and warrant consideration as candidates for preventing endometrial cancer development by tamoxifen in humans treated with this anticancer drug.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
authors.forename: Lucie
authors.initials: L
authors.lastname: Borek-Dohalská
authors.forename: Petr
authors.initials: P
authors.lastname: Hodek
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Mráz
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D065607:Cytochrome P-450 Enzyme Inhibitors; D018736:DNA Adducts; D016889:Endometrial Neoplasms / Q000188:drug therapy; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D009153:Mutagens; D010100:Oxygen / Q000378:metabolism; D011817:Rabbits; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: C461381:2-isopropenyl-2-methyladamantane; C461382:3-isopropenyl-3-methyldiamantane; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D009153:Mutagens; D013629:Tamoxifen; D000547:Amantadine; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C050356:steroid 15-alpha-hydroxylase; C025619:steroid 16-beta-hydroxylase; D000218:Adamantane; D010100:Oxygen