Protection from CCI 4 toxicity by prestimulation of hepatocellular regeneration in partially hepatectomized gerbils

Abstract

The present investigation was undertaken to test our hypothesis that the slow responses of hepatocellular regeneration and tissue repair after CCl 4-induced liver injury are responsible for the high sensitivity of gerbils to the hepatotoxic and lethal effects of CCl 4. These studies were conducted in normal and actively regenerating livers using male gerbils 5 or 15 days after partial (2/3) hepatectomy (PH 5 and PH 15, respectively), or those undergoing sham operation (SH). An ld 50 dose of CCl 4 (80 μL/ kg, i.p.) resulted in a mortality (21%) significantly (P < 0.05) less than 50% in PH 5 gerbils 48 hr after CCl 4 administration, whereas the mortality observed in PH 15 or SH gerbils was not significantly different from 50%. The elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly (P < 0.05) less in PH 5 gerbils than in PH 15 or SH groups after the administration of either the ld 50 dose or a low dose (15 μL/kg) of CCl 4. Histopathological and histomorphometric examinations also indicated that CCl 4-induced liver injury was less severe in PH 5 gerbils than in the PH 15 and SH groups. The hepatic microsomal cytochrome P450 content measured before CCl 4 administration in the PH 5 gerbils was decreased (26%) significantly (P < 0.05) as compared with the SH group, but was not significantly different from that of PH 15 gerbils. In vivo metabolism of 14CCl 4 and lipid peroxidation in liver tissue were not significantly different among the various groups. Therefore, the protection against CCl 4 toxicity observed in PH 5 gerbils is unlikely to be due to decreased bioactivation of CCl 4 or lipid peroxidation in that group. [ 3H]Thymidine incorporation into hepatocellular nuclear DNA was 4- to 5-fold higher in PH 5 gerbils than in the PH 15 and SH groups, indicating active hepatocellular proliferation in PH 5 gerbils. [ 3H]Thymidine incorporation was further increased significantly (P < 0.05) 24 hr after challenge with a low dose of CCl 4 in PH 5 gerbils, whereas it remained low until 48 hr after the CCl 4 injection in the PH 15 or SH group. The protection against CCl 4 toxicity afforded by partial hepatectomy was closely associated with active hepatocellular regeneration. The overall results confirm the concept that the high sensitivity of gerbils to CCl 4 is due to very sluggish hepatocellular regeneration and tissue repair response to the CCl 4-induced liver injury.