Chanas Brian, Wang Hongbing, Ghanayem Burhan I
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Toxicol Appl Pharmacol. 2003 Dec 1;193(2):293-302. doi: 10.1016/j.taap.2003.08.006.
Acrylonitrile (AN) is a potent toxicant and a known rodent carcinogen. AN epoxidation to cyanoethylene oxide (CEO) via CYP2E1 and its subsequent metabolism via epoxide hydrolases (EH) to yield cyanide is thought to be responsible for the acute toxicity and mortality of AN. Recent reports showed that male mice are more sensitive than females to the acute toxicity/mortality of AN. The present work was undertaken to assess the metabolic and enzymatic basis for the greater sensitivity of male vs female mice to AN toxicity. Male and female wild-type and CYP2E1-null mice received AN at 0, 2.5, 10, 20, or 40 mg/kg by gavage. Cyanide concentrations were measured at 1 or 3 h after dosing. Current data demonstrated that cyanide levels in blood and tissues of AN-treated wild-type mice of both sexes were significantly greater than in vehicle-treated controls and increased in a dose-dependent manner. In contrast, cyanide levels in AN-treated CYP2E1-null mice were not statistically different from those measured in vehicle-treated controls. Furthermore, higher levels of cyanide were detected in male wild-type mice vs females in association with greater sensitivity of males to the acute toxicity/mortality of this chemical. Using Western blot analysis, negligible difference in CYP2E1 expression with higher levels of soluble and microsomal EH (sEH and mEH) was detected in the liver of male vs female mice. In kidneys, male mice exhibited higher expression of both renal CYP2E1 and sEH than did female mice. In conclusion, higher blood and tissue cyanide levels are responsible for the greater sensitivity of male vs female mice to AN. Further, higher expression of CYP2E1 and EH in male mice may contribute to greater formation of CEO and its subsequent metabolism to yield cyanide, respectively.
丙烯腈（AN）是一种强效毒物，也是一种已知的啮齿动物致癌物。人们认为，AN通过细胞色素P450 2E1（CYP2E1）环氧化生成氰基环氧乙烷（CEO），随后经环氧水解酶（EH）代谢产生氰化物，这是AN产生急性毒性和致死性的原因。最近的报告显示，雄性小鼠对AN的急性毒性/致死性比雌性小鼠更敏感。本研究旨在评估雄性小鼠比雌性小鼠对AN毒性更敏感的代谢和酶学基础。雄性和雌性野生型及CYP2E1基因敲除小鼠经口给予0、2.5、10、20或40 mg/kg的AN。给药后1或3小时测量氰化物浓度。目前的数据表明，经AN处理的两性野生型小鼠血液和组织中的氰化物水平显著高于溶剂处理的对照组，且呈剂量依赖性增加。相比之下，经AN处理的CYP2E1基因敲除小鼠中的氰化物水平与溶剂处理的对照组相比无统计学差异。此外，与雄性小鼠对该化学物质的急性毒性/致死性更高的敏感性相关，雄性野生型小鼠中检测到的氰化物水平高于雌性。使用蛋白质免疫印迹分析，在雄性和雌性小鼠肝脏中检测到CYP2E1表达差异可忽略不计，但可溶性和微粒体EH（sEH和mEH）水平较高。在肾脏中，雄性小鼠的肾CYP2E1和sEH表达均高于雌性小鼠。总之，血液和组织中较高的氰化物水平是雄性小鼠比雌性小鼠对AN更敏感的原因。此外，雄性小鼠中CYP2E1和EH的较高表达可能分别导致CEO的生成增加及其随后代谢产生氰化物。
