Role of Hepatocellular Regeneration in CCl 4 Autoprotection

Abstract

The destruction of liver microsomal cytochromes P₄₅₀ by a previously administered low dose of CCl₄ has been widely accepted as the mechanism of CCl₄ autoprotection. However, circumstantial evidence suggests that this mechanism cannot completely explain the phenomenon of autoprotection. The protective effect of a low dose of CCl₄ (0.3 ml/kg, po) on the lethal effect of a subsequently administered high dose (5 ml/kg, po) was established in male Sprague Dawley rats. The protective dose permitted 100% survival, whereas only 15% survival was observed without it. Hepatotoxicity, measured by serum enzyme elevations (aspartate transaminase, alanine transaminase, and sorbitol dehydrogenase) and histopathological changes 24 hr after the treatment with high dose, was similar in both the groups, even though the protective dose had significantly decreased liver microsomal cytochromes P₄₅₀ (to 62% of normal) and associated enzymes, aminopyrine demethylase and aniline hydroxylase. Rats pretreated with CoCl₂ to decrease hepatic microsomal cytochrome P₄₅₀ to 44% of normal levels did not show a significant protection from the hepatotoxicity of high dose of CCl₄. Previous studies have established that hepatocellular regeneration is stimulated within 6 hr after the administration of a low dose of CCl₄. Based on this observation, a premise that autoprotection results from augmented recovery from injury rather than decreased injury appears likely. Hence, the role of hepatocellular regeneration was evaluated by following ³H-thymidine incorporation in hepatocellular nuclear DNA, labelling index by autoradiography, and by morphometric estimation of mitotic index. After administration of the protective dose of CCl₄, stimulated nuclear DNA synthesis measured by ³H-thymidine incorporation into nuclear DNA was increased and this remained high even after subsequent administration of high dose of CCl₄. Forty-eight hr after the administration of a lethal dose of CCl₄ alone (5 ml/kg, po), labelling index was slightly increased, but mitotic index was not increased. In the surviving rats (15%), both labelling index and mitotic index were significantly elevated after an additional 24 hr. In rats receiving the protective dose, a significantly greater elevation of labelling index as well as mitotic index occurred 48 hr after the administration of the same lethal dose of CCl₄. These results suggest that hepatocellular regeneration stimulated by the protective dose, as a biological response recruited to overcome the accompanying limited injury, may augment and sustain tissue repair processes to permit tissue restoration even after the massive liver injury elicited by the subsequent large dose of CCl₄.

Keywords

Liver regeneration mechanism of autoprotection toxicity carbon tetrachloride rats cobalt chloride destruction of cytochrome P450

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