STIMULATED TISSUE-REPAIR PREVENTS LETHALITY IN ISOPROPANOL-INDUCED POTENTIATION OF CARBON-TETRACHLORIDE HEPATOTOXICITY

Published reports on the alcohol potentiation of CCl4 toxicity indicat e that in spite of enhanced hepatotoxicity there is no increase in let hality. The objective of this study was to investigate the mechanism i nvolved in animal survival despite significantly enhanced liver injury . Male Sprague-Dawley rats (175-225 g) were treated with isopropanol ( ISOP, 2.5 ml/kg, 25% aqueous solution, po) 24 hr prior to CCl4 (1 ml/k g, ip) administration, Plasma enzymes (ALT and SDH), hepatic glycogen levels, and [H-3]-thymidine (H-3-T) incorporation into hepatonuclear D NA were measured during a time course (0-96 hr) after CCl4 administrat ion, Liver sections were examined for histopathology and cell cycle pr ogression by proliferating cell nuclear antigen (PCNA) immunohistochem istry. Maximum injury was observed at 36 hr in both the groups as indi cated by elevated plasma enzyme levels and by histopathology. The exte nt of injury in the ISOP + CCl4 group was higher than that in the H2O + CCl4 group, Plasma enzyme activity returned to control levels by 60 hr, indicating recovery from injury in both groups, Maximum H-3-T inco rporation occurred at 48 hr in both groups (ISOP + CCl4; vehicle + CCl 4), indicating maximum stimulation of S-phase synthesis, PCNA studies revealed a corresponding stimulation of cell cycle progression. The wa ve of S-phase synthesis and cell cycle progression returned to control levels in the H2O +/- CCl4 group by 60 hr but continued up to 72 hr i n the ISOP + CCl4 group, These findings support the hypothesis that in response to increased infliction of CCl4 injury by isopropanol, augme nted stimulation of cell division and tissue repair restrain the progr ession of injury and restore hepatic structure and function, thereby a llowing the rats to survive, Further, antimitotic intervention with co lchicine (1 mg/kg, ip) led to decreased S-phase synthesis, followed by 60% lethality in the isopropanol-pretreated group in contrast to 40% lethality in the group receiving CCl4 alone (H2O +/- CCl4). These find ings suggest that greater stimulation of tissue repair restrains the p rogression of ISOP-enhanced infliction of CCl4 liver injury and accoun ts for recovery from enhanced liver injury and animal survival. The fi ndings are consistent with a two-stage model of toxicity wherein liver injury is linked by progression or regression of injury, which is gov erned by the extent of tissue repair to the final outcome. (C) 1996 Ac ademic Press, Inc.