Jacob S, Abdel-Aziz A A, Shouman S A, Ahmed A E
Department of Pathology, University of Texas Medical Branch, Galveston 77555-0609, USA. sjacob.utmb.edu
Toxicol Ind Health. 1998 Jul-Aug;14(4):533-46. doi: 10.1177/074823379801400404.
Chloroacetonitrile (CAN), a drinking water disinfectant by-product, has mutagenic and carcinogenic properties. CAN is known to deplete glutathione (GSH), and previous studies reported an enhanced molecular interaction of CAN after GSH depletion in the uterine and fetal tissues of mice. The present report may help to understand the potential mechanisms involved in such molecular interactions by examining the disposition, transplacental uptake and covalent interaction of the chemical in normal and GSH depleted pregnant mice (at 13th day of gestation). Both normal and GSH depleted (by administration of Diethylmaleate (DEM), 0.6 mL/kg, i.p.) pregnant mice were given an equitoxic i.v. dose of 2-[14C]-CAN(333 microCi/kg equivalent to 77 mg/kg). Animals were processed for whole-body autoradiography (WBA) at 1, 8 and 24 hr after treatment. Tissue distribution of radioactivity in the autoradiographs was quantitated using computer aided image analysis. With few exceptions, a rapid high uptake (at 1 hr) of radioactivity was observed in all major maternal (liver, lung, urinary bladder, gastrointestinal mucosa, cerebellum, uterine luminal fluid) and fetal (liver, brain) organs of both normal and GSH depleted mice. This pattern of distribution was observed, with lesser intensity, at 8 hr following treatment. At a later time period (24 hr), there was a significant higher retention and covalent interaction of radioactivity in GSH depleted mouse tissues especially in the liver as compared to normal mouse. This study suggests that 2-[14C]-CAN and/or its metabolites are capable of crossing the placental barrier. The observed higher uptake and retention of the radioactivity in the maternal liver, kidney, cerebellum, nasal turbinates and fetal liver may pose toxicity of the chemical to these organs. The increased covalent interaction of radioactivty in GSH depleted mice liver may indicate the potential utilization of GSH pathway by this organ in the detoxication of CAN derived metabolites and thus exerting hepatotoxicity.
氯乙腈（CAN）是一种饮用水消毒副产物，具有致突变和致癌特性。已知CAN会消耗谷胱甘肽（GSH），先前的研究报道，在小鼠子宫和胎儿组织中GSH耗竭后，CAN的分子相互作用增强。本报告通过研究该化学物质在正常和GSH耗竭的妊娠小鼠（妊娠第13天）中的处置、经胎盘摄取和共价相互作用，可能有助于了解此类分子相互作用的潜在机制。正常和GSH耗竭（通过腹腔注射0.6 mL/kg马来酸二乙酯（DEM））的妊娠小鼠均静脉注射等毒性剂量的2-[14C]-CAN（333微居里/千克，相当于77毫克/千克）。处理后1、8和24小时对动物进行全身放射自显影（WBA）。使用计算机辅助图像分析对放射自显影片中放射性的组织分布进行定量。除少数例外，正常和GSH耗竭小鼠的所有主要母体器官（肝脏、肺、膀胱、胃肠道黏膜、小脑、子宫腔液）和胎儿器官（肝脏、脑）在处理后1小时均观察到放射性的快速高摄取。处理后8小时观察到这种分布模式，但强度较小。在较晚的时间段（24小时），与正常小鼠相比，GSH耗竭小鼠组织中尤其是肝脏中放射性的保留和共价相互作用显著更高。本研究表明2-[14C]-CAN和/或其代谢产物能够穿过胎盘屏障。在母体肝脏、肾脏、小脑、鼻甲和胎儿肝脏中观察到的放射性较高摄取和保留可能对这些器官造成该化学物质的毒性。GSH耗竭小鼠肝脏中放射性共价相互作用的增加可能表明该器官在CAN衍生代谢产物解毒过程中潜在地利用了GSH途径，从而发挥肝毒性。
