OBJECTIVE Cytochrome P450(CYP)2J2 is highly expressed in many kinds of human tumors and promotes tumor cell growth via regulating the metabolism of arachidonic acids.The purposes of this study were toidentify the new ...OBJECTIVE Cytochrome P450(CYP)2J2 is highly expressed in many kinds of human tumors and promotes tumor cell growth via regulating the metabolism of arachidonic acids.The purposes of this study were toidentify the new inhibitor of CYP2J2 from natural compounds and evaluate its potential to inhibit hepatoma carcinoma cells.METHODS Total fifty natural products were screened for the inhibitory potency against the activity of CYP2J2-mediated astemizole O-demethylation via LCMS/MS analysis.Enzyme kinetic and molecular docking studies were also carried out.RESULTS Our data found that plumbagin potently inhibited CYP2J2 with IC50value at 3.42,3.37 and 1.17μmol·L-1in rat liver microsomes,human liver microsomes(HLMs)and recombinant CYP2J2(rC YP2J2),respectively.Further enzyme kinetic studies showed that plumbagin was a mixed-type inhibitor of CYP2J2 in HLMs and r CYP2J2 with Kivalues of 1.88and 0.92μmol·L-1,respectively.Docking data presented that plumbagin interacted with CYP2J2 mainly through GLU222 and ALA223,which were crucial residues for substrates binding.At the same time,plumbagin showed cytotoxicity effects on hepatic carcinoma cell lines,such as HepG 2 and SMMC-7721,with IC50values at 11.55±1.06and(13.15±1.11)μmol·L-1,respectively.CONCLUSION These results indicated that plumbagin was a potent CYP2J2 inhibitor and potential anticancer agent.Further studies are needed to cover the mechanism of its antitumor activity.展开更多
基金The project supported by National Natural Science Foundation of China(81301908)the Science and Technology Commission of Shanghai Municipality(15140904700,13ZR1412600 and 14DZ2270100)
文摘OBJECTIVE Cytochrome P450(CYP)2J2 is highly expressed in many kinds of human tumors and promotes tumor cell growth via regulating the metabolism of arachidonic acids.The purposes of this study were toidentify the new inhibitor of CYP2J2 from natural compounds and evaluate its potential to inhibit hepatoma carcinoma cells.METHODS Total fifty natural products were screened for the inhibitory potency against the activity of CYP2J2-mediated astemizole O-demethylation via LCMS/MS analysis.Enzyme kinetic and molecular docking studies were also carried out.RESULTS Our data found that plumbagin potently inhibited CYP2J2 with IC50value at 3.42,3.37 and 1.17μmol·L-1in rat liver microsomes,human liver microsomes(HLMs)and recombinant CYP2J2(rC YP2J2),respectively.Further enzyme kinetic studies showed that plumbagin was a mixed-type inhibitor of CYP2J2 in HLMs and r CYP2J2 with Kivalues of 1.88and 0.92μmol·L-1,respectively.Docking data presented that plumbagin interacted with CYP2J2 mainly through GLU222 and ALA223,which were crucial residues for substrates binding.At the same time,plumbagin showed cytotoxicity effects on hepatic carcinoma cell lines,such as HepG 2 and SMMC-7721,with IC50values at 11.55±1.06and(13.15±1.11)μmol·L-1,respectively.CONCLUSION These results indicated that plumbagin was a potent CYP2J2 inhibitor and potential anticancer agent.Further studies are needed to cover the mechanism of its antitumor activity.
