Role of cytochrome P450 2E1 in the metabolism of acrylamide and acrylonitrile in mice.
Role of cytochrome P450 2E1 in the metabolism of acrylamide and acrylonitrile in mice.
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DOI：
10.1021/tx990040k
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发表时间：
1999-10
影响因子：
4.1
通讯作者：
S. Sumner;T. Fennell;T. Moore;B. Chanas;F. J. Gonzalez;B. Ghanayem
中科院分区：
文献类型：
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作者：
S. Sumner;T. Fennell;T. Moore;B. Chanas;F. J. Gonzalez;B. Ghanayem
丙烯腈（AN）和丙烯酰胺（AM）通常用于合成塑料和聚合物。在啮齿类动物中，AM和AN分别代谢为环氧化物缩水甘油酰胺和氰基环氧乙烷。本研究的目的是确定细胞色素P450在AM和AN体内代谢中的作用。野生型（WT）小鼠、用氨基苯并三唑（ABT，50 mg/kg ip，暴露前2 h）预处理的WT小鼠和缺乏细胞色素P450 2 E1（P450 2 E1-null）的小鼠用50 mg/kg [（13）C]AM po处理。WT小鼠和P450 2 E1-null小鼠用2.5或10 mg/kg [（13）C]AN po处理。收集尿液24小时，并使用（13）C NMR表征代谢物。WT小鼠分泌的代谢产物来源于环氧化物和GSH与AM或AN的直接结合。在ABT预处理的WT小鼠和P450 2 E1缺失小鼠的尿液中，仅观察到GSH与AM或AN直接结合的代谢产物。根据这些剂量下尿代谢物的评价，这些数据表明，P450 2 E1可能是参与AM和AN在小鼠体内代谢的唯一细胞色素P450酶，抑制总P450活性不会导致AM的非P450代谢的新途径，缺乏P450 2 E1的小鼠不分泌由其他细胞色素P450氧化产生的AM或AN代谢物。P450 2 E1-null小鼠可能是研究氧化代谢在这些化合物的毒性或致癌性中的作用的合适模型。
Acrylonitrile (AN) and acrylamide (AM) are commonly used in the synthesis of plastics and polymers. In rodents, AM and AN are metabolized to the epoxides glycidamide and cyanoethylene oxide, respectively. The aim of this study was to determine the role of cytochrome P450 in the metabolism of AM and AN in vivo. Wild-type (WT) mice, WT mice pretreated with aminobenzotriazole (ABT, 50 mg/kg ip, 2 h pre-exposure), and mice devoid of cytochrome P450 2E1 (P450 2E1-null) were treated with 50 mg/kg [(13)C]AM po. WT mice and P450 2E1-null mice were treated with 2.5 or 10 mg/kg [(13)C]AN po. Urine was collected for 24 h, and metabolites were characterized using (13)C 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 P450 2E1-null mice. On the basis of evaluation of urinary metabolites at these doses, these data suggest that P450 2E1 is possibly the only cytochrome P450 enzyme involved in the metabolism of AM and AN in mice, that inhibiting total P450 activity does not result in new pathways of non-P450 metabolism of AM, and that mice devoid of P450 2E1 do not excrete metabolites of AM or AN that would be produced by oxidation by other cytochrome P450s. P450 2E1-null mice may be an appropriate model for the investigation of the role of oxidative metabolism in the toxicity or carcinogenicity of these compounds.