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[PMID]: | 28461575 |
[Au] Autor: | Phuc NM; Wu Z; O Y; Lee JH; Oh S; Song GY; Liu KH |
[Ad] Endereço: | BK21 Plus KNU Multi-Omics-Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea (N.M.P., Z.W., K.-H.L.); College of Pharmacy, Chungnam National University, Daejeon, Korea (Y.O., J.-H.L., G.-Y.S.); and Dep |
[Ti] Título: | LKY-047: First Selective Inhibitor of Cytochrome P450 2J2. |
[So] Source: | Drug Metab Dispos;45(7):765-769, 2017 Jul. | [Is] ISSN: | 1521-009X |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7 )-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro- -pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole -demethylase and terfenadine hydroxylase activity, with values of 0.96 and 2.61 M, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a value of 3.61 M. Preincubation of LKY-047 with HLMs and NADPH did not alter inhibition potency, indicating that it is not a mechanism-based inhibitor. LKY-047 was found to be a selective CYP2J2 inhibitor with no inhibitory effect on other human P450s, such as CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A (IC > 50 M). These in vitro data support the use of LKY-047 as a selective CYP2J2 inhibitor with potential application in the identification of P450 isoforms responsible for drug metabolism in reaction phenotyping assays. |
[Mh] Termos MeSH primário: |
Inibidores das Enzimas do Citocromo P-450/farmacologia Sistema Enzimático do Citocromo P-450/metabolismo
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[Mh] Termos MeSH secundário: |
Seres Humanos Hidroxilação/efeitos dos fármacos Inativação Metabólica/efeitos dos fármacos Microssomos Hepáticos/efeitos dos fármacos Microssomos Hepáticos/metabolismo NADP/metabolismo Isoformas de Proteínas/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Protein Isoforms); 53-59-8 (NADP); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (arachidonate epoxygenase) |
[Em] Mês de entrada: | 1803 |
[Cu] Atualização por classe: | 180307 |
[Lr] Data última revisão:
| 180307 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170503 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1124/dmd.117.075036 |
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