Chakrabarti S, Brodeur J
J Toxicol Environ Health. 1984;14(2-3):379-91. doi: 10.1080/15287398409530587.
Male Sprague-Dawley rats received an intraperitoneal injection of 0.25-, 0.5-, 1.0-, 2.5-, and 5.0-mmol/kg dose of bromobenzene in corn oil. The metabolic fate of bromobenzene was studied by measuring its various urinary metabolites 24 h following bromobenzene administration. The hepatotoxicity of bromobenzene was estimated by determination of the serum glutamic-oxaloacetic and glutamic-pyruvic transaminase activities (SGOT and SGPT) 24 h after dosing. Treatment of rats with bromobenzene at up to 0.5 mmol/kg did not influence the transaminase activities, but significant increases in such activities began to manifest at a dose of 1 mmol/kg. However, no further increase in hepatotoxic response was induced on exposure to higher doses (2.5 and 5.0 mmol/kg) of bromobenzene. The urinary excretion of toxic doses of bromobenzene was nonlinear, based on the quantitative composition of various urinary metabolites. Furthermore, the fraction of the dose converted to thioethers, p-bromophenol, m-bromophenol, and total phenolic metabolites decreased with increasing toxic dose, suggesting their formation to be capacity-limited. The ratios of thioethers to total phenolic metabolites, of thioethers to p-bromophenol, and of thioethers to o-bromophenol decreased with increasing dose of bromobenzene. The correlation of the dose-dependent fate of metabolic excretion of bromobenzene with the results of the dose-hepatotoxic response curves supports the conclusion that there exists an apparent threshold dose (approximately 1-2.5 mmol/kg) for the toxic effects of bromobenzene that coincides with saturation of the metabolic pathways involving both glutathione/glutathione S-transferase(s) and formation of certain phenolic derivatives for its detoxification. All these results further suggest a role of a saturable, metabolic activation process involving 3,4-epoxide rather than 2,3-epoxide of bromobenzene in the development of its hepatotoxicity.
雄性Sprague-Dawley大鼠腹腔注射0.25、0.5、1.0、2.5和5.0 mmol/kg剂量的溴苯（溶于玉米油）。在给予溴苯24小时后，通过测量其各种尿液代谢物来研究溴苯的代谢命运。通过给药24小时后测定血清谷草转氨酶和谷丙转氨酶活性（SGOT和SGPT）来评估溴苯的肝毒性。用高达0.5 mmol/kg的溴苯处理大鼠不会影响转氨酶活性，但在剂量为1 mmol/kg时，这些活性开始显著增加。然而，暴露于更高剂量（2.5和5.0 mmol/kg）的溴苯时，肝毒性反应并未进一步增加。基于各种尿液代谢物的定量组成，有毒剂量溴苯的尿液排泄是非线性的。此外，随着有毒剂量的增加，转化为硫醚、对溴苯酚、间溴苯酚和总酚类代谢物的剂量分数降低，表明它们的形成受容量限制。硫醚与总酚类代谢物的比率、硫醚与对溴苯酚的比率以及硫醚与邻溴苯酚的比率随着溴苯剂量的增加而降低。溴苯代谢排泄的剂量依赖性命运与剂量-肝毒性反应曲线结果之间的相关性支持了这样的结论，即溴苯的毒性作用存在一个明显的阈值剂量（约1 - 2.5 mmol/kg），这与涉及谷胱甘肽/谷胱甘肽S-转移酶以及形成某些酚类衍生物进行解毒的代谢途径饱和相吻合。所有这些结果进一步表明，在溴苯肝毒性的发展过程中，涉及3,4-环氧化物而非2,3-环氧化物的可饱和代谢激活过程发挥了作用。
