Kodavanti P R, Joshi U M, Mehendale H M, Lockard V G
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216.
J Appl Toxicol. 1989 Dec;9(6):367-75. doi: 10.1002/jat.2550090602.
Our previous studies indicated the involvement of some unidentified mechanisms, apart from the bioactivation phenomenon, in chlordecone (CD)-potentiated CCl4 hepatotoxicity and lethality. Recent studies revealed that hepatocellular regeneration is suppressed in CD + CCl4 toxicity. The present work is a continuation of our earlier work employing a partial hepatectomy model for stimulating hepatocellular division, in normal (N) or CD-treated (10 ppm for 15 days) rats. Male Sprague-Dawley rats maintained on an appropriate dietary protocol and undergoing sham (SH) or partial hepatectomies (PH) were employed. Hepatocellular regeneration was assessed by measuring the percentage mitotic figures and by autoradiography of liver sections from rats given 3H-thymidine in vivo. Hepatotoxicity was assessed by examining liver sections for necrotic cells, swollen cells and cells having lipid droplets. CCl4 (100 microliters kg-1)-induced histopathological alterations in CD-pretreated rats were significantly decreased in rats 2 days post-PH (PH2) as compared to SH rats or rats 7 days post-PH (PH7), indicating that amplification of CCl4 toxicity is significantly reduced when there is a greater regenerative activity. The percentage of mitoses as well as the percentage of labelled cells were significantly elevated at 2-6 h after CCl4 administration in N rats but remained suppressed in CD rats. In CD-pretreated PH2 rats where the percentage of mitoses and the percentage of labelled cells were many-fold greater when compared to SH or PH7 rats, a portion of the stimulated hepatocellular division decreased significantly at 2-6 h after CCl4 administration, but remained significantly greater when compared to basal level of regeneration.(ABSTRACT TRUNCATED AT 250 WORDS)
我们之前的研究表明，除生物活化现象外，某些未知机制也参与了十氯酮（CD）增强的四氯化碳（CCl4）肝毒性和致死性。最近的研究显示，在CD + CCl4毒性作用下，肝细胞再生受到抑制。本研究是我们早期工作的延续，采用部分肝切除术模型来刺激正常（N）或经CD处理（10 ppm，持续15天）大鼠的肝细胞分裂。选用雄性Sprague-Dawley大鼠，使其维持适当的饮食方案，并进行假手术（SH）或部分肝切除术（PH）。通过测量有丝分裂指数以及对体内注射3H-胸腺嘧啶核苷的大鼠肝脏切片进行放射自显影来评估肝细胞再生。通过检查肝切片中的坏死细胞、肿胀细胞和有脂滴的细胞来评估肝毒性。与SH大鼠或PH术后7天（PH7）的大鼠相比，CD预处理大鼠在PH术后2天（PH2）时，CCl4（100微升/千克）诱导的组织病理学改变显著减少，这表明当再生活性增强时，CCl4毒性的放大作用显著降低。N大鼠在CCl4给药后2 - 6小时，有丝分裂百分比以及标记细胞百分比显著升高，但在CD大鼠中仍受到抑制。在CD预处理的PH2大鼠中，与SH或PH7大鼠相比，有丝分裂百分比和标记细胞百分比高出许多倍，在CCl4给药后2 - 6小时，部分受刺激的肝细胞分裂显著减少，但与基础再生水平相比仍显著更高。（摘要截短于250字）
