COMPARATIVE METABOLISM AND MECHANISMS OF TOXICITY OF NTP CHEMICALS

NTP 化学品的比较代谢和毒性机制

• 批准号: 6290076
• 负责人: BURHAN I GHANAYEM
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290076
• 关键词: biotransformation; breath tests; cyanides; cytochrome P450; drug metabolism; enzyme activity; laboratory mouse; liver metabolism; toxicology; urinalysis

Cytochrome P450 (CYP) enzymes carry out oxidative metabolism of a variety of endogenous and foreign chemicals. Cytochrome P450 2E1 (CYP2E1) is thought to be responsible for the oxidative metabolism of ethanol and a number of other chemicals of importance to the NTP including 1,3-butadiene, benzene, and vinyl chloride. The aim of the present work is to assess the role of CYP2E1 in the oxidative metabolism and toxicity of acrylonitrile (AN), methacrylonitrile (MAN), and acrylamide (AM) was determined. Wild-type mice (WT), WT mice pretreated with aminobenzotriazole (ABT, 50 mg/kg ip, 2 hr pre- exposure), and mice devoid of cytochrome P450 2E1 (CYP2E1-null) were administered 50 mg/kg [13C]AM po. WT mice and CYP2E1-null mice were administered 2.5 or 10 mg/kg [13C]AN po. Urine was collected for 24 hr, and metabolites were characterized using 13C NMR. WT mice excreted metabolites derived from the epoxides and from direct GSH conjugation with AM or AN. Only metabolites derived from direct GSH conjugation with AM or AN were observed in the urine from ABT-pretreated WT mice and CYP2E1-null mice. - CYP2E1-null mice Acrylonitirle Methacrylonitrile Acrylamide 2-Butoxyethanol Metabolism Disposition

细胞色素P450（CYP）酶对各种内源性和外源化学物质进行氧化代谢。细胞色素P450 2E1（CYP2E1）被认为是乙醇的氧化代谢以及对NTP重要性的氧化代谢，包括1,3-丁二烯，苯，苯和乙烯基氯。本工作的目的是评估CYP2E1在丙烯腈（AN），甲基丙烯腈（MAN）和丙烯酰胺（AM）中的氧化代谢和毒性中的作用。野生型小鼠（WT），WT小鼠用氨基杂联三位唑（ABT，50 mg/kg IP，2小时的暴露前）和没有细胞色素P450 2E1（CYP2E1-NULL）的小鼠施用。施用2.5或10 mg/kg的WT小鼠和CYP2E-NULL小鼠[13C]收集尿液24小时，并使用13C NMR表征代谢物。 WT小鼠排出源自环氧化物的代谢产物以及与Am或An的直接GSH结合。仅在ABT预处理的WT小鼠和CYP2E1-NULL小鼠的尿液中观察到源自与AM或A的直接GSH共轭的代谢产物。 -CYP2E1-NULL小鼠丙烯酸甲基丙烯腈丙烯酰胺2-丁氧基乙醇代谢处置