【作者】 赵丽娇； 杨顺莉； 钟儒刚；

【Author】 Lijiao Zhao;Shunli Yang;Rugang Zhong;Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology;

【机构】 北京工业大学生命科学与生物工程学院北京市环境与病毒肿瘤学重点实验室；

【摘要】 亚硝胺是一类重要致癌物质,在体内细胞色素P450的作用下经代谢活化生成活泼亲电试剂,导致DNA碱基的烷化损伤最终诱发癌症。因此,P450催化亚硝胺的代谢活化是其致癌过程的关键步骤。采用密度泛函理论对P450活性中心铁卟啉催化亚硝胺代谢活化的反应机理进行了研究。结果表明,P450催化亚硝胺羟基化的过程包含两个步骤——氢抽提反应和回弹反应;其中,氢抽提反应为控速步骤。羟基化过程中高自旋态(HS)和低自旋态(LS)均参与反应,整个羟基化过程呈现明显的双态反应性(TSR)。比较了亚硝胺分子侧链上C~α-H和C~β-H羟基化反应的差异,结果表明C~α-H比C~β-H更易于在P450作用下发生羟基化。本研究为深入揭示亚硝胺经代谢活化导致癌症的作用机制提供了可靠的理论依据。更多还原

【Abstract】 Nitrosamines(NAs) are an important family of carcinogens.They are metabolic activated by cytochrome P450 in vivo to generate active electrophiles, which alkylate DNA bases and lead to the occurrence of cancer.Therefore, P450-catalyzed metabolic activation is a pivotal step in the carcinogenesis of NAs.In this study, the metabolic mechanism of NAs catalyzed by the active center of P450, ferric porphyrin, was investigated using density functional theory(DFT) computations.The results indicated that the hydroxylation of NAs included two steps, hydrogen abstraction and rebound reaction; and the hydrogen abstraction is the rate-limiting step.High-and low-spin states of ferric porphyrin equally participate the hydroxylation of NAs, which exhibits obvious characters of two-state reactivity(TSR).The hydroxylation mechanisms of C~α-H and C~β-H in the side chain of NAs were compared.The results suggested that the hydroxylation of C~α-H was more favorable than C~β-H.This research provides plausible explanation for the mechanism of metabolic activation and carcinogenesis of N-nitrosamines.更多还原