ROLE OF TISSUE-REPAIR IN CARBON-TETRACHLORIDE HEPATOTOXICITY IN MALE AND FEMALE SPRAGUE-DAWLEY AND WISTAR RATS

This study was designed to assess the hypothesis that large difference s between male and female Wistar and Sprague-Dawley rats in susceptibi lity 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 o f rats were administered a minimum lethal dose (LD(10)) of CCl4, 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 CCl4 and evaluated in terms of the rate and magnitude of damage and the effici ency of repair activities. The mortality for Wistar rats was high for both males (70%) and females (90%) treated with CLC at 24 h after CCl4 administration but fell to 33% for females while remaining high (67%) for males treated with CLC at 48 h after CCl4 administration, Both ma le and female Sprague-Dawley rats also exhibited a high mortality rate (70-80%) when administered CLC 24 h after CCl4. 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 CCl4 dose, Male and female Wistar and Sprague-Dawley rats were dos ed with CCl4 (0.3 ml/kg, 1:1, vol/vol in corn oil, i.p.), and the alan ine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were monitored at 0, 23, 38, and 72 h after treatment. In the Sprague -Dawley strain, AST and ALT values were markedly increased in the fema le as compared with the male at 24, 38, and 72 h. Both sexes displayed decreasing serum enzyme values starting at 38 h. In contrast to Sprag ue-Dawley rats, male Wistar rats showed progressive increases and sign ificantly higher ASTIALT values than the females at 48 h; conversely, by 48 h the female rats were starting to display decreasing serum enzy me levels indicative of tissue repair. The findings support the hypoth esis that the enhanced susceptibility to CCl4-induced hepatotoxicity o f 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 CCl4-induced hepatotoxicity is most likely related to its greater susceptibility for the production of liver dam age rather than a less efficient tissue-repair process.