El Hadri L, Chanas B, Ghanayem B I
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, MD (B3-10), Research Triangle Park, NC 27709, USA.
Toxicol Appl Pharmacol. 2005 Jun 1;205(2):116-25. doi: 10.1016/j.taap.2004.10.002. Epub 2004 Nov 25.
Methacrylonitrile (MAN) and acrylonitrile (AN) are metabolized via glutathione (GSH) conjugation or epoxide formation. We have recently shown that CYP2E1 is essential for AN epoxidation and subsequent cyanide liberation. Current studies were designed to compare the enzymatic basis of MAN vs. AN metabolism to cyanide using wild-type (WT), CYP2E1-, and mEH-null mice. Mice received a single gavage dose of 0.047, 0.095, 0.19, or 0.38 mmol/kg of MAN or AN, and blood cyanide was measured at 1 or 3 h later. Blood cyanide levels in WT mice treated with AN or MAN were dose and time dependent. At equimolar doses, significantly higher levels of cyanide were detected in the blood of MAN- vs. AN-treated mice. Further, while significant reduction in blood cyanide levels occurred in MAN-treated CYP2E1-null vs. WT mice, AN metabolism to cyanide was largely abolished in CYP2E1-null mice. Pretreatment of mice with 1-aminobenzotriazole (ABT, CYP inhibitor) demonstrated that CYPs other than CYP2E1 also contribute to MAN metabolism to cyanide. Blood cyanide levels in mEH-null mice treated with aliphatic nitriles are generally lower than levels in similarly treated WT mice. Western blot analysis showed that expression of sEH was greater in male vs. female mice. The role of various epoxide hydrolases (EHs) in the production of cyanide from aliphatic nitriles is apparently structure and dose dependent. Regardless of genotype, significantly higher levels of cyanide were measured in the blood of male vs. female mice treated with MAN or AN. In conclusion, these data showed that (1) at equimolar doses, higher blood cyanide levels were detected in mice treated with MAN vs. AN; (2) while CYP2E1 is the only enzyme responsible for AN metabolism to cyanide, other CYPs also contribute to MAN metabolism; and (3) significantly higher levels of cyanide were measured in the blood of male vs. female treated with either nitrile. Higher blood cyanide levels in male vs. female mice and in MAN- vs. AN-treated mice may explain the gender-related differences in the toxicity of these chemicals and the greater potency of MAN vs. AN.
甲基丙烯腈（MAN）和丙烯腈（AN）通过谷胱甘肽（GSH）结合或环氧化物形成进行代谢。我们最近表明，CYP2E1对于AN环氧化及随后的氰化物释放至关重要。当前研究旨在使用野生型（WT）、CYP2E1基因敲除和mEH基因敲除小鼠比较MAN与AN代谢为氰化物的酶学基础。小鼠单次灌胃给予0.047、0.095、0.19或0.38 mmol/kg的MAN或AN，并在1或3小时后测量血氰化物水平。用AN或MAN处理的WT小鼠的血氰化物水平呈剂量和时间依赖性。在等摩尔剂量下，与用AN处理的小鼠相比，用MAN处理的小鼠血液中检测到的氰化物水平显著更高。此外，虽然在用MAN处理的CYP2E1基因敲除小鼠与WT小鼠中血氰化物水平显著降低，但在CYP2E1基因敲除小鼠中，AN代谢为氰化物的过程基本被消除。用1-氨基苯并三唑（ABT，CYP抑制剂）预处理小鼠表明，除CYP2E1外的其他CYPs也参与MAN代谢为氰化物的过程。用脂肪族腈处理的mEH基因敲除小鼠的血氰化物水平通常低于同样处理的WT小鼠。蛋白质免疫印迹分析表明，sEH在雄性小鼠中的表达高于雌性小鼠。各种环氧化物水解酶（EHs）在脂肪族腈产生氰化物过程中的作用显然具有结构和剂量依赖性。无论基因型如何，用MAN或AN处理的雄性小鼠血液中测量到的氰化物水平均显著高于雌性小鼠。总之，这些数据表明：（1）在等摩尔剂量下，与用AN处理的小鼠相比，用MAN处理的小鼠血液中检测到更高的血氰化物水平；（2）虽然CYP2E1是AN代谢为氰化物的唯一酶，但其他CYPs也参与MAN的代谢；（3）用任何一种腈处理的雄性小鼠血液中测量到的氰化物水平均显著高于雌性小鼠。雄性与雌性小鼠以及用MAN与用AN处理的小鼠之间血氰化物水平较高，这可能解释了这些化学物质毒性方面与性别相关的差异以及MAN相对于AN更强的毒性。
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