Pilon D, Roberts A E, Rickert D E
Department of Biochemical Toxicology and Pathobiology, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Toxicol Appl Pharmacol. 1988 Sep 15;95(2):265-78. doi: 10.1016/0041-008x(88)90163-9.
Cellular GSH may influence the metabolism of the rodent brain and forestomach carcinogen acrylonitrile (ACN) and its subsequent binding to tissue macromolecules. To investigate the role of GSH in ACN metabolism and binding to macromolecules, we studied the effect of GSH depletion on the irreversible association of radiolabel with tissue macromolecules in male F-344 rats given a 4 mg/kg dose of [2,3-14C]ACN by inhalation. A combined phorone/buthionine sulfoximine treatment (300 mg/kg and 2 mmol/kg, respectively) was given 30 minutes prior to ACN exposure to deplete GSH. The uptake of ACN vapor by control rats was biphasic and characterized by a rapid phase lasting about 60 min and by a slower phase from 60 min to the end of exposure. The rate of uptake for both phases was linearly related to the initial concentration of ACN in the chamber. GSH depletion caused an increase in the rate of ACN uptake in both phases. It also caused a decrease in total radioactivity recovered in brain, stomach, liver, kidney, and blood and a concomitant decrease in the ACN-derived nondialyzable radioactivity in these organs. In control rats, accumulation of radiolabel was greatest in brain RNA, but no radioactivity was detected in DNA of any organ examined. In GSH-depleted rats, the radiolabel concentration was higher in brain RNA than in the liver or stomach RNA, but was also 50% lower than that observed in brain RNA of control rats. Urinary excretion of thiocyanate (SCN-), a metabolite derived from the epoxide pathway of ACN metabolism, was doubled in GSH-depleted rats. These results suggest that GSH might be involved in the distribution of ACN-derived reactive species and, therefore, might play a role in the binding of ACN-derived species to tissue macromolecules and nucleic acids.
细胞内谷胱甘肽（GSH）可能影响啮齿动物脑和前胃致癌物丙烯腈（ACN）的代谢及其随后与组织大分子的结合。为了研究GSH在ACN代谢及与大分子结合中的作用，我们通过吸入给予雄性F-344大鼠4mg/kg剂量的[2,3-¹⁴C]ACN，研究了GSH耗竭对放射性标记物与组织大分子不可逆结合的影响。在ACN暴露前30分钟给予联合的佛尔酮/丁硫氨酸亚砜胺处理（分别为300mg/kg和2mmol/kg）以耗尽GSH。对照大鼠对ACN蒸气的摄取呈双相性，其特征为持续约60分钟的快速相和从60分钟到暴露结束的较慢相。两个相的摄取速率均与舱室内ACN的初始浓度呈线性相关。GSH耗竭导致两个相中ACN摄取速率增加。它还导致脑、胃、肝、肾和血液中回收的总放射性降低，以及这些器官中ACN衍生的不可透析放射性随之降低。在对照大鼠中，放射性标记物在脑RNA中的积累最多，但在所检查的任何器官的DNA中均未检测到放射性。在GSH耗竭的大鼠中，脑RNA中的放射性标记物浓度高于肝或胃RNA，但也比对照大鼠脑RNA中观察到的浓度低50%。硫氰酸盐（SCN⁻）是ACN代谢环氧途径衍生的一种代谢产物，其在GSH耗竭大鼠中的尿排泄量增加了一倍。这些结果表明，GSH可能参与ACN衍生的活性物质的分布，因此可能在ACN衍生的物质与组织大分子和核酸的结合中起作用。
