Protection of Hepatotoxic and Lethal Effects of CCl by Partial Hepatectomy

CCl 4 is a hepatotoxic haloalkane, capable of producing hepatocellular fatty degeneration and centrilobular necrosis. Previous reports indicate induction of liver regeneration after 36-48 hr of CCl 4 treatment, which is considered as a secondary effect. The present investigation was undertaken to evaluate the primary effects of CCl 4 on hepatic DNA synthesis and to correlate liver regeneration with CCl 4 toxicity. These studies were conducted in normal and actively regenerating livers using male Sprague-Dawley rats undergoing sham operation (SH), or partial (70%) hepatectomy (PH). Incorporation of 3 H-thymidine ( 3 H-T) in hepatocellular nuclear DNA and autoradiographic analyses of liver sections served as indices for hepatocellular regeneration. Initial experiments established that peak regeneration occurs at 2 days post-PH (PH 2 ) and liver regeneration phases out by 7 days post-PH (PH 7 ). SH and PH rats were challenged with a single ip dose of either corn oil vehicle or CCl 4 at either 0.1 ml/kg (to represent subtoxic dose) or 2.5 ml/kg (to represent toxic dose). The low dose of CCl 4 was not toxic and did not alter 3 H-T incorporation and percentage labelled cells at 6 or 24 hours after administration to SH, PH 2 or PH 7 groups, indicating that there was no interference with PH-stimulated hepatocellular regeneration. The high dose of CCl 4 was significantly hepatotoxic and lethal in SH rats, while in PH 2 rats both hepatotoxic and lethal effects were significantly decreased. 3 H-T incorporation as well as percentage labelled cells, highly stimulated by PH, were significantly decreased by high dose of CCl 4 . However, hepatocellular regeneration in PH 2 rats treated with high dose of CCl 4 was still significantly higher than SH or PH, groups by virtue of the stronger stimulatory effect of PH. In PH 7 rats, where hepatocellular regeneration had returned to the SH level, the hepatotoxic and lethal effects of the large dose of CCl 4 were also restored. These findings show that the progressive phase of a single high dose of CCl 4 injury which normally culminates in hepatotoxic and lethal effects is significantly mitigated by previously stimulated hepatocellular regeneration. High dose of CCl 4 suppresses hepatocellular regeneration at early time points after administration in contrast to the smaller subtoxic dose of CCl 4 . By virtue of the much stronger stimulatory effect, PH results in the protection against the hepatotoxic and lethal effects of CCl 4 despite the obtunding effects of the high dose on hepatocellular regeneration.