New selective inhibitors of cytochromes P450 2B and their application to antimutagenesis of tamoxifen
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
12061800
DOI
10.1016/s0003-9861(02)00259-x
PII: S0003-9861(02)00259-X
Knihovny.cz E-zdroje
- MeSH
- adamantan analogy a deriváty farmakologie MeSH
- adukty DNA MeSH
- aktivace enzymů MeSH
- amantadin farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- aromatické hydroxylasy * MeSH
- chemické modely MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory cytochromu P450 * MeSH
- inhibitory enzymů farmakologie MeSH
- kinetika MeSH
- králíci MeSH
- kyslík metabolismus MeSH
- lidé MeSH
- mikrozomy účinky léků metabolismus MeSH
- mutageny * MeSH
- nádory endometria farmakoterapie MeSH
- steroidhydroxylasy antagonisté a inhibitory MeSH
- tamoxifen farmakologie MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 2-isopropenyl-2-methyladamantane MeSH Prohlížeč
- 3-isopropenyl-3-methyldiamantane MeSH Prohlížeč
- adamantan MeSH
- adukty DNA MeSH
- amantadin MeSH
- antitumorózní látky MeSH
- aromatické hydroxylasy * MeSH
- inhibitory cytochromu P450 * MeSH
- inhibitory enzymů MeSH
- kyslík MeSH
- mutageny * MeSH
- steroid 15-alpha-hydroxylase MeSH Prohlížeč
- steroid 16-beta-hydroxylase MeSH Prohlížeč
- steroidhydroxylasy MeSH
- tamoxifen MeSH
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.
Citace poskytuje Crossref.org
