Plummer J L, Hall P M, Ilsley A H, Jenner M A, Cousins M J
Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Bedford Park, Australia.
Pharmacol Toxicol. 1990 Oct;67(4):329-35. doi: 10.1111/j.1600-0773.1990.tb00839.x.
Rats were exposed for four weeks either to air or to vapours of chloroform, carbon tetrachloride or 1,1-dichloroethylene given either as a constant concentration (continuous profile) or as repeated exposures for 6 hr per day, 5 days per week (fluctuating profile). Vapour concentrations were used such that the total exposure (concentration x time) was the same for the two profiles. Within each group, some animals received the enzyme-inducing agents, phenobarbitone or 1,3-butanediol, in their drinking water. Separate experiments were conducted to determine the influence of enzyme inducers and vapour concentration on chlorocarbon uptake and metabolism. In the case of chloroform, hepatic injury was more severe in animals exposed to constant vapour concentration, while dichloroethylene was more toxic when given as a fluctuating profile, especially in butanediol-treated rats. Carbon tetrachloride hepatotoxicity was similar in the two exposure profiles but was exacerbated by butanediol treatment. Butanediol-treated animals in the fluctuating profile group showed evidence of developing cirrhosis. These results could not be fully explained on the basis of the effect of enzyme inducers and exposure profile on amount of agent metabolized. Both the amount of toxic metabolites and the temporal pattern of their formation appear to be important determinants of liver injury.
将大鼠暴露于空气或氯仿、四氯化碳或1,1 - 二氯乙烯蒸气中四周，这些蒸气以恒定浓度（连续模式）或每周5天、每天6小时的重复暴露（波动模式）给予。使用的蒸气浓度使得两种模式下的总暴露量（浓度×时间）相同。在每组中，一些动物在饮用水中摄入酶诱导剂苯巴比妥或1,3 - 丁二醇。进行了单独的实验以确定酶诱导剂和蒸气浓度对氯代烃摄取和代谢的影响。就氯仿而言，暴露于恒定蒸气浓度的动物肝脏损伤更严重，而1,1 - 二氯乙烯以波动模式给予时毒性更大，尤其是在经丁二醇处理的大鼠中。两种暴露模式下四氯化碳的肝毒性相似，但丁二醇处理会使其加剧。波动模式组中经丁二醇处理的动物出现了肝硬化的迹象。这些结果不能完全基于酶诱导剂和暴露模式对代谢的试剂数量的影响来解释。有毒代谢物的数量及其形成的时间模式似乎都是肝损伤的重要决定因素。
