RESUMO
The inhibition of ethoxy coumarin O-deethylase (ECOD) activity by aucubin and its aglycone was examined in a microsomal system and in freshly isolated hepatocytes. Aucubin was found to be inactive but the aglycone was found to be a potent time-dependent inhibitor of ECOD activity in both systems. The close structural similarity between the aglycone of aucubin and glutaraldehyde suggests a similar mechanism of enzyme inhibition through protein cross-linking by Schiff reactions. The similarity between the 2 compounds was demonstrated through their closely similar binding spectra to bovine serum albumin. The biological activities reported for the aglycone are suggested to be due to this similarity to glutaraldehyde.
Assuntos
O-Dealquilase 7-Alcoxicumarina/antagonistas & inibidores , Inibidores das Enzimas do Citocromo P-450 , Glucosídeos/farmacologia , Iridoides , Animais , Bovinos , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/metabolismo , Reagentes de Ligações Cruzadas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Glucosídeos/química , Glucosídeos/metabolismo , Glutaral/química , Técnicas In Vitro , Glucosídeos Iridoides , L-Lactato Desidrogenase/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ligação Proteica , Piranos/química , Piranos/metabolismo , Piranos/farmacologia , Ratos , Ratos Wistar , Bases de Schiff/química , Bases de Schiff/metabolismo , Bases de Schiff/farmacologia , Soroalbumina Bovina/metabolismo , Espectrofotometria UltravioletaRESUMO
1. The naturally occurring hepatoprotective compound silybin is a potent inhibitor of glutathione S-transferase isoenzymes 1-1, 2-2, 3-3, and 4-4, displaying a high degree of isoenzyme selectivity. 2. Using CDNB at a fixed concentration of 1 mM and varying the GSH concentration, silybin exhibited competitive inhibition of isoenzyme 2-2 with a Ki of 32 microM, non-competitive and predominantly non-competitive inhibition of isoenzymes 1-1 and 4-4 with Kis of 20 and 1.2 microM, respectively, and uncompetitive inhibition of isoenzyme 3-3 with a Ki of 0.2 microM. 3. With CDNB as the variable concentration substrate silybin exhibited competitive inhibition of isoenzyme 1-1 with a Ki of 8 microM, non-competitive inhibition of isoenzyme 2-2 with a Ki of 41 microM, and non-competitive inhibition of isoenzymes 3-3 and 4-4 with Kis of 0.8 and 0.5 microM, respectively.
