Kulkarni S G, Duong H, Gomila R, Mehendale H M
Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209-0470, USA.
Arch Toxicol. 1996;70(11):714-23. doi: 10.1007/s002040050332.
Fischer 344 (F344) rats are reportedly 75-fold more sensitive than Sprague Dawley (S-D) rats to 1,2-dichlorobenzene (o-DCB) hepatotoxicity. Lethality studies were conducted since no information was available regarding the ultimate consequence of this sensitivity in terms of animal survival in the two strains. LD50S for o-DCB (1.66 ml/kg and 1.76 ml/kg in male F344 and S-D rats, respectively) did not differ. Several studies have shown the importance of tissue repair on animal survival following exposure to toxic chemicals. The objective of this study was to investigate if differential rates of cell division and tissue repair might explain the lack of difference in LD50 dose between the two strains despite higher hepatotoxic injury in F344 rats. Age-matched male S-D and F344 rats were administered o-DCB (0.2, 0.6, 1.2 ml/kg, i.p.); injury and tissue repair occurring as two dynamic but opposing events were measured over time. Liver injury was assessed by measuring plasma alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities and by liver histopathology. Higher plasma ALT elevations were observed in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. Using SDH as a marker of liver injury, the strain difference was evident only at 0.2 ml o-DCB/kg. Liver regeneration was estimated by 3H-thymidine incorporation into hepatonuclear DNA and via proliferating cell nuclear antigen (PCNA) assay. Prompt and significantly higher hepatocellular regeneration beginning at 36 h was evident in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. The significantly higher depletion of hepatic glycogen observed in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg occurred without significant changes in plasma glucose and is consistent with highly stimulated tissue repair seen in these rats at the corresponding doses. However, increasing the dose further to 1.2 ml o-DCB/kg results in a delayed (S-phase synthesis begins at 48 h) and diminished response to o-DCB. These findings suggest that a significantly higher rate of tissue repair in F344 rats helps them overcome higher liver injury inflicted by o-DCB. This differential in tissue repair in the two strains may play a vital role in equalizing the ultimate outcome of toxicity in the two strains.
据报道，Fischer 344（F344）大鼠对1,2 - 二氯苯（邻二氯苯，o - DCB）肝毒性的敏感性比Sprague Dawley（S - D）大鼠高75倍。由于尚无关于这种敏感性对两种品系动物生存最终影响的信息，因此进行了致死率研究。o - DCB的半数致死剂量（LD50）在雄性F344大鼠和S - D大鼠中分别为1.66 ml/kg和1.76 ml/kg，二者并无差异。多项研究表明，组织修复对动物接触有毒化学物质后的生存至关重要。本研究的目的是调查细胞分裂和组织修复的不同速率是否可以解释尽管F344大鼠肝毒性损伤更严重，但两种品系之间LD50剂量却没有差异。将年龄匹配的雄性S - D和F344大鼠腹腔注射o - DCB（0.2、0.6、1.2 ml/kg）；随着时间推移，测量作为两个动态但相反事件发生的损伤和组织修复情况。通过测量血浆丙氨酸转氨酶（ALT）和山梨醇脱氢酶（SDH）活性以及进行肝脏组织病理学检查来评估肝损伤。在给予0.2和0.6 ml o - DCB/kg后，F344大鼠的血浆ALT升高幅度更大。以SDH作为肝损伤标志物时，品系差异仅在给予0.2 ml o - DCB/kg时明显。通过将3H - 胸腺嘧啶掺入肝细胞核DNA以及通过增殖细胞核抗原（PCNA）测定来估计肝脏再生情况。在给予0.2和0.6 ml o - DCB/kg后，F344大鼠在36小时开始出现迅速且显著更高的肝细胞再生。在给予0.2和0.6 ml o - DCB/kg后，F344大鼠肝脏糖原的显著更高消耗在血浆葡萄糖无显著变化的情况下发生，这与在相应剂量下这些大鼠中观察到的高度刺激的组织修复一致。然而，将剂量进一步增加到1.2 ml o - DCB/kg会导致对o - DCB的反应延迟（S期合成在48小时开始）且减弱。这些发现表明，F344大鼠中显著更高的组织修复速率有助于它们克服o - DCB造成的更严重肝损伤。两种品系在组织修复方面的这种差异可能在使两种品系中毒性的最终结果趋于平衡方面发挥至关重要的作用。
