Aimová Dagmar, Stiborová Marie
Department of Biochemistry, Charles University, Albertov 2030, Prague 2, Czech Republic.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005 Dec;149(2):437-40.
Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Recently, we found that ellipticine also forms the cytochrome P450 (CYP)-mediated covalent DNA adducts. Here, we study the effect of ellipticine on CYP enzymes in rat hepatic microsomes, studying its binding to the enzymes and its potential to inhibit the CYP activities measured with their selective substrates. Although ellipticine was reported to be a selective and strong inhibitor of CYP1A1/2, we found that its inhibitory potential is non-specific. Ellipticine is the most potent inhibitor for CYP3A-dependent 6beta-hydroxylation of progesterone, followed by CYP1A1/2-dependent ethoxyresorufin O-deethylation and CYP2B-mediated pentoxyresorufin O-depentylation. Lower inhibition was detected for 1'-hydroxylation of bufurarol, 21-hydroxylation of progesterone and 6-hydroxylation of chlorzoxazone catalyzed by CYP2D, CYP2C and CYP2E1, respectively. Ellipticine binds to several CYPs of rat hepatic microsomes. The binding titration of ellipticine typically give reverse type I spectrum with CYPs in rat hepatic microsomes. The results indicate that inhibition of CYPs by ellipticine cannot be explained only by its differential potency to bind to individual CYPs.
椭圆玫瑰树碱是一种强效抗肿瘤药物，其作用模式被认为主要基于DNA嵌入和/或拓扑异构酶II的抑制。最近，我们发现椭圆玫瑰树碱还能形成细胞色素P450（CYP）介导的共价DNA加合物。在此，我们研究椭圆玫瑰树碱对大鼠肝微粒体中CYP酶的影响，研究其与这些酶的结合情况以及用其选择性底物测定的抑制CYP活性的潜力。尽管据报道椭圆玫瑰树碱是CYP1A1/2的选择性强抑制剂，但我们发现其抑制潜力是非特异性的。椭圆玫瑰树碱是孕酮CYP3A依赖性6β-羟基化的最有效抑制剂，其次是CYP1A1/2依赖性乙氧基亚香豆素O-脱乙基化和CYP2B介导的戊氧基亚香豆素O-脱戊基化。对于分别由CYP2D、CYP2C和CYP2E1催化的布库洛尔1'-羟基化、孕酮21-羟基化和氯唑沙宗6-羟基化，检测到的抑制作用较低。椭圆玫瑰树碱与大鼠肝微粒体的几种CYP结合。椭圆玫瑰树碱的结合滴定通常在大鼠肝微粒体中与CYP产生反向I型光谱。结果表明，椭圆玫瑰树碱对CYP的抑制作用不能仅用其与单个CYP结合的差异效力来解释。
