New selective inhibitors of cytochromes P450 2B and their application to antimutagenesis of tamoxifen
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
12061800
DOI
10.1016/s0003-9861(02)00259-x
PII: S0003-9861(02)00259-X
Knihovny.cz E-resources
- MeSH
- Adamantane analogs & derivatives pharmacology MeSH
- DNA Adducts MeSH
- Enzyme Activation MeSH
- Amantadine pharmacology MeSH
- Aryl Hydrocarbon Hydroxylases * MeSH
- Models, Chemical MeSH
- Inhibitory Concentration 50 MeSH
- Cytochrome P-450 Enzyme Inhibitors * MeSH
- Enzyme Inhibitors pharmacology MeSH
- Kinetics MeSH
- Rabbits MeSH
- Oxygen metabolism MeSH
- Humans MeSH
- Microsomes drug effects metabolism MeSH
- Mutagens * MeSH
- Endometrial Neoplasms drug therapy MeSH
- Antineoplastic Agents pharmacology MeSH
- Steroid Hydroxylases antagonists & inhibitors MeSH
- Tamoxifen pharmacology MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Humans MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2-isopropenyl-2-methyladamantane MeSH Browser
- 3-isopropenyl-3-methyldiamantane MeSH Browser
- Adamantane MeSH
- DNA Adducts MeSH
- Amantadine MeSH
- Aryl Hydrocarbon Hydroxylases * MeSH
- Cytochrome P-450 Enzyme Inhibitors * MeSH
- Enzyme Inhibitors MeSH
- Oxygen MeSH
- Mutagens * MeSH
- Antineoplastic Agents MeSH
- steroid 15-alpha-hydroxylase MeSH Browser
- steroid 16-beta-hydroxylase MeSH Browser
- Steroid Hydroxylases 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.
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