Dalich G M, Larson R E
Fundam Appl Toxicol. 1985 Feb;5(1):105-16. doi: 10.1016/0272-0590(85)90054-5.
Time- and dose-dependent correlations of monochlorobenzene (CB) hepatotoxic effects were studied in view of (1) assumed mechanistic similarities to bromobenzene (BB), (2) the paucity of these data for CB, and (3) the relatively greater environmental importance of CB compared with BB. An ip dosage of 9.8 mmol/kg CB (approximately equal to LD10) produced evidence of liver toxicity over a 72-hr time course. Sulfobromophthalein (BSP) retention was maximized 3-16 hr post-treatment and normalized after 72 hr, whereas plasma alanine aminotransferase activity (ALT) and morphological evidence of damage were maximized about 48 hr after dosing. Maximal covalent binding to liver protein (3.07 nmol/mg) had occurred by 24 hr and approximately 36% of the administered dose had appeared in the urine by 48 hr. Liver and plasma CB concentrations were proportionally increased over the dosage range 2.0-14.7 mmol/kg but marked centrolobular necrosis and ALT elevations were seen only at the two highest dosages (9.8 and 14.7 mmol/kg). On the other hand, all doses depressed hepatic glutathione (GSH) to between 30 and 40% of control by 4 hr. Evidence of rapid recovery was evident at 2.0 and 4.9 mmol/kg but GSH levels remained low through 8 hr after 9.8 or 14.7 mmol/kg. Liver/body weight ratios were increased to a similar extent at all dosages when measured 24 hr post-treatment. Urinary excretion ranged from 59% at the low dosage to only 19% at the highest dosage by 24 hr. Dose-related covalent binding to liver protein at 24 hr occurred up to 9.8 mmol/kg but the binding associated with 14.7 mmol/kg was equivalent to that seen with the 4.9 mmol/kg dosage (1.6 nmol/mg protein). Cytochrome P-450 levels were depressed to between 50 and 80% of control 24 hr post-treatment with no clear dose relationship. While the hepatotoxic effects of CB and BB appear similar, these data suggest that some mechanistic differences are involved.
鉴于（1）假设一氯苯（CB）与溴苯（BB）在作用机制上具有相似性，（2）CB的此类数据较少，以及（3）与BB相比，CB在环境方面具有相对更大的重要性，因此研究了CB肝毒性作用的时间和剂量依赖性相关性。腹腔注射剂量为9.8 mmol/kg的CB（约等于LD10），在72小时的时间进程中产生了肝毒性证据。磺溴酞钠（BSP）潴留量在治疗后3 - 16小时达到最大值，并在72小时后恢复正常，而血浆丙氨酸转氨酶活性（ALT）和损伤的形态学证据在给药后约48小时达到最大值。到24小时时，与肝蛋白的共价结合达到最大值（3.07 nmol/mg），到48小时时，约36%的给药剂量出现在尿液中。在2.0 - 14.7 mmol/kg的剂量范围内，肝脏和血浆中CB浓度成比例增加，但仅在两个最高剂量（9.8和14.7 mmol/kg）时观察到明显的中央小叶坏死和ALT升高。另一方面，所有剂量在4小时时均将肝脏谷胱甘肽（GSH）降低至对照值的30%至40%。在2.0和4.9 mmol/kg时，快速恢复的迹象明显，但在9.8或14.7 mmol/kg后8小时内，GSH水平仍保持较低。治疗后24小时测量时，所有剂量下肝脏/体重比均有相似程度的增加。到24小时时，尿液排泄量从低剂量时的59%到高剂量时的仅19%不等。在24小时时，与肝蛋白的剂量相关共价结合在高达9.8 mmol/kg时均有发生，但与14.7 mmol/kg相关的结合与4.9 mmol/kg剂量时观察到的结合相当（1.6 nmol/mg蛋白）。治疗后24小时，细胞色素P - 450水平降低至对照值的50%至80%，且无明显的剂量关系。虽然CB和BB的肝毒性作用似乎相似，但这些数据表明其中涉及一些作用机制上的差异。
