Ahmed A E, Hussein G I, Loh J P, Abdel-Rahman S Z
Department of Pathology, University of Texas Medical Branch, Galveston 77550.
J Biochem Toxicol. 1991 Summer;6(2):115-21. doi: 10.1002/jbt.2570060205.
The haloacetonitrile, dibromoacetonitrile (DBAN), is a direct-acting genotoxic agent that has been detected in drinking water. In a time course study, male Sprague-Dawley rats were treated with DBAN (75 mg/kg PO), and killed at 0.5, 1, 2, and 4 hr after treatment. In a dose response study, animals were treated orally with various doses of DBAN (25, 50, 75, and 100 mg/kg) and killed at one-half hour after treatment. Control animals received 1 ml/kg PO of the vehicle dimethyl sulfoxide (DMSO). In both experiments blood and organs were collected and stored at -80 degrees C until the time of analysis. At 0.5 hr after treatment, a single oral dose of DBAN caused a significant decrease of glutathione (GSH) concentrations in liver (54% of control) and stomach (6% of control). Hepatic GSH depletion was maximal at 0.5 hr and rebound to the control levels by 4 hr. In contrast, gastric GSH concentrations remained low at all time points. DBAN caused an insignificant change in both kidney and blood GSH levels. DBAN significantly inhibited glutathione-S-transferase (GST) activity in liver and stomach. Hepatic GST inhibition was maximal (34% of control) at 2 hr and minimal (80% of control) at 4 hr. Meanwhile, in the stomach GST activity was inhibited at 1 hr (60% of control) and remained low at all times after treatment. Both GSH depletion and GST inhibition were dose-dependent. This study indicates that GSH and GST play an important role in the metabolism and detoxification of DBAN in rats. The prolonged depletion of GSH and inhibition of GST in the gastrointestinal (GI) tissues suggest that the GI tract is a major target for DBAN toxicity.
卤代乙腈，二溴乙腈（DBAN），是一种已在饮用水中检测到的直接作用的基因毒性剂。在一项时间进程研究中，雄性斯普拉格 - 道利大鼠经口给予DBAN（75毫克/千克），并在给药后0.5、1、2和4小时处死。在一项剂量反应研究中，动物经口给予不同剂量的DBAN（25、50、75和100毫克/千克），并在给药后半小时处死。对照动物经口给予1毫升/千克的溶媒二甲基亚砜（DMSO）。在这两个实验中，采集血液和器官并储存在 -80摄氏度直至分析时。给药后0.5小时，单次口服剂量的DBAN导致肝脏（对照组的54%）和胃（对照组的6%）中谷胱甘肽（GSH）浓度显著降低。肝脏GSH消耗在0.5小时达到最大，并在4小时反弹至对照水平。相比之下，胃中GSH浓度在所有时间点都保持较低。DBAN导致肾脏和血液中GSH水平的变化不显著。DBAN显著抑制肝脏和胃中的谷胱甘肽 - S - 转移酶（GST）活性。肝脏GST抑制在2小时达到最大（对照组的34%），在4小时最小（对照组的80%）。同时，胃中GST活性在1小时被抑制（对照组的60%），给药后一直保持较低水平。GSH消耗和GST抑制均呈剂量依赖性。这项研究表明，GSH和GST在大鼠体内DBAN的代谢和解毒中起重要作用。胃肠道（GI）组织中GSH的长期消耗和GST的抑制表明胃肠道是DBAN毒性的主要靶点。
