Younis H S, Hoglen N C, Kuester R K, Gunawardhana L, Sipes I G
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona 85721-2466, USA.
Toxicol Appl Pharmacol. 2000 Mar 1;163(2):141-8. doi: 10.1006/taap.1999.8860.
1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in male Fischer 344 (F-344) rats but not in Sprague-Dawley (SD) rats. While Kupffer cell-dependent oxidative stress plays a role in the progression of 1,2-DCB-mediated liver injury, we hypothesize that initiation of liver injury is due to oxidative events within the hepatocyte. This study compared hepatocellular oxidative stress marked by glutathione disulfide (GSSG) and glutathione (GSH) production in either bile, liver, or isolated hepatocytes of F-344 and SD rats following 1,2-DCB administration. Hepatic GSH concentrations were depleted at a greater rate in F-344 than in SD rats within 12 h of 1,2-DCB administration (3.6 mmol/kg ip). In bile, GSSG concentrations were threefold greater in F-344 rats compared to SD rats by 9 h of 1,2-DCB treatment. Moreover, 1-aminobenzotriazole but not gadolinium chloride pretreatment blocked the rise in biliary GSSG concentrations following 1,2-DCB administration. In in vitro studies, isolated hepatocytes of F-344 rats had a 15% increase in cellular GSSG concentrations following 1 h of 1,2-DCB (3.55 nmol) exposure, while GSH decreased 22% by 6.5 h compared to controls. In contrast, isolated SD hepatocytes exposed to 1,2-DCB had no increase in GSSG and only an 8% reduction in GSH. Furthermore, parameters of lipid peroxidation were increased in F-344 rats and not in SD rats. Collectively, these data suggest that hepatocellular oxidative stress is dependent upon bioactivation and the enhanced oxidative stress in the F-344 rat may explain its susceptibility to 1,2-DCB compared to the SD rat.
1,2-二氯苯（1,2-DCB）对雄性Fischer 344（F-344）大鼠是一种强效肝毒剂，但对Sprague-Dawley（SD）大鼠则不然。虽然库普弗细胞依赖性氧化应激在1,2-DCB介导的肝损伤进展中起作用，但我们推测肝损伤的起始是由于肝细胞内的氧化事件。本研究比较了1,2-DCB给药后F-344和SD大鼠胆汁、肝脏或分离肝细胞中以谷胱甘二肽（GSSG）和谷胱甘肽（GSH）产生为标志的肝细胞氧化应激。在1,2-DCB（3.6 mmol/kg腹腔注射）给药后12小时内，F-344大鼠肝脏GSH浓度的消耗速度比SD大鼠更快。在胆汁中，1,2-DCB处理9小时后，F-344大鼠的GSSG浓度比SD大鼠高两倍。此外，1-氨基苯并三唑而非氯化钆预处理可阻断1,2-DCB给药后胆汁中GSSG浓度的升高。在体外研究中，F-344大鼠分离的肝细胞在暴露于1,2-DCB（3.55 nmol）1小时后，细胞内GSSG浓度增加15%，而与对照组相比，GSH在6.5小时时减少22%。相比之下，暴露于1,2-DCB的SD分离肝细胞中GSSG没有增加，GSH仅减少8%。此外，F-344大鼠的脂质过氧化参数增加，而SD大鼠则没有。总体而言，这些数据表明肝细胞氧化应激取决于生物活化，与SD大鼠相比，F-344大鼠增强的氧化应激可能解释了其对1,2-DCB的易感性。
