新型抗脑瘤化合物CAT3的体外代谢研究

Metabolism of a promising anti-tumor agent CAT3 in vitro

CAT3是一种新型抗脑瘤化合物,在Daoy和U87MG裸鼠原位异种移植模型中具有强效抗瘤活性,但其代谢机制尚不清楚。本研究考察了CAT3在小鼠/犬/人全血和肝微粒体、人源化重组酶等温孵体系中的代谢特征,所有动物福利和动物实验遵循中国医学科学院动物伦理委员会规定。研究结果表明CAT3在小鼠/犬/人全血中可水解为活性代谢物PF403,丁酰胆碱酯酶、羧酸酯酶和丝氨酸水解酶参与其生成,代谢速率存在种属差异小鼠>人>犬;应用CYPs同工酶的选择性抑制剂、人源化重组酶研究结果表明,CYP1A2、1A1、2C9和3A4是参与M1(氧化脱水),M2(双氧化脱水),M3(甲基化氧化脱水),M4(氧化),M5(脱甲基)生成的主要同工酶,CYP2B6、2C8、2C19和2D6等亚型也有少量参与;Ⅱ相酶UGT1A1、1A3、1A9可催化PF403生成葡萄糖醛酸化代谢物GLU-PF403。以上结果提示,CAT3代谢是多酶参与的生物转化过程,代谢酶介导的药物相互作用值得临床关注。

CAT3 is a promising anti-brain tumor agent that has significant anti-tumor activity on Daoy or U87 MG orthotopic xenograft in nude mice.This study was carried out to investigate the metabolic profiles of CAT3 in mouse/dog/human blood and microsome as well as in humanized recombinant enzymes.All animal care and experimental procedures were reviewed and approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences.Our findings showed that CAT3 could be hydrolyzed to active metabolite PF403 by carboxy‐lesterase,butyrylcholinesterase and serine hydrolase in mouse/dog/human blood.PF403 could be further metabo‐lized to M1 oxidative dehydration product,M2 double oxidation dehydration product,M3 methylation oxidative dehydration product,M4 oxidation product and M5 demethylation product,which were mainly catalyzed by CYP1 A2,1 A1,2 C9 and 3 A4,and slightly by CYP2 B6,2 C8,2 C19 and 2 D6.Besides oxidative metabolism,PF403 also was transformed into glucuronylation metabolites GLU-PF403 by Phase II enzymes UGT1 A1,1 A3 and 1 A9.Taken together,the metabolism of CAT3 was a multiple enzyme catalytic reaction.These results could provide valuable information for potential enzyme-mediated DDI in clinic studies.