Role of Tissue Repair in Carbon Tetrachloride Hepatotoxicity in Male and Female Sprague-Dawley and Wistar Rats

Abstract

This study was designed to assess the hypothesis that large differences between male and female Wistar and Sprague-Dawley rats in susceptibility to carbon tetrachloride (CCl4)-induced hepatotoxicity are related to the differential capacity to repair tissue damage. This hypothesis was evaluated via two complementary approaches, (a) Separate groups of rats were administered a minimum lethal dose (LD10) of CC14, with colchicine (CLC) given at 24, 48, or 72 h after CCl4, and assessed for survival, (b) Rats were given a modestly hepatotoxic dose of CC14 and evaluated in terms of the rate and magnitude of damage and the efficiency of repair activities. The mortality for Wistar rats was high for both males (70%) and females (90%) treated with CLC at 24 h after CC14 administration but fell to 33% for females while remaining high (67%) for males treated with CLC at 48 h after CC14 administration. Both male and female Sprague-Dawley rats also exhibited a high mortality rate (70–80%) when administered CLC 24 h after CC14. As in the Wistar rats, the mortality in the Sprague-Dawley females declined to 36% while it remained high among males (67%) when CLC was administered 48 h after the CC14 dose. Male and female Wistar and Sprague-Dawley rats were dosed with CC14 (0.3 ml/kg, 1:1, vol/vol in corn oil, i.p.), and the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were monitored at 0, 24, 48, and 72 h after treatment. In the Sprague-Dawley strain, AST and ALT values were markedly increased in the female as compared with the male at 24, 48, and 72 h. Both sexes displayed decreasing serum enzyme values starting at 48 h. In contrast to Sprague-Dawley rats, male Wistar rats showed progressive increases and significantly higher AST/ALT values than the females at 48 h; conversely, by 48 h the female rats were starting to display decreasing serum enzyme levels indicative of tissue repair. The findings support the hypothesis that the enhanced susceptibility to CCl4-induced hepatotoxicity of the male compared with the female Wistar rat is principally due to a slower capacity for hepatic tissue repair. In contrast, the principal cause for the enhanced susceptibility of the female compared with the male Sprague-Dawley rat to CC14-induced hepatotoxicity is most likely related to its greater susceptibility for the production of liver damage rather than a less efficient tissue-repair process. Key Words: Carbon tetrachloride-Hepatotoxicity-Sex differences-Tissue repair