Stimulated tissue repair prevents lethality in isopropanol-induced potentiation of carbon tetrachloride hepatotoxicity

Published reports on the alcohol potentiation of CCl4 toxicity indicate that in spite of enhanced hepatotoxicity there is no increase in lethality. The objective of this study was to investigate the mechanism involved 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/kg, ip) administration, Plasma enzymes (ALT and SDH), hepatic glycogen levels, and [H-3]-thymidine (H-3-T) incorporation into hepatonuclear DNA were measured during a time course (0-96 hr) after CCl4 administration, Liver sections were examined for histopathology and cell cycle progression by proliferating cell nuclear antigen (PCNA) immunohistochemistry. Maximum injury was observed at 36 hr in both the groups as indicated by elevated plasma enzyme levels and by histopathology. The extent 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 incorporation occurred at 48 hr in both groups (ISOP + CCl4; vehicle + CCl4), indicating maximum stimulation of S-phase synthesis, PCNA studies revealed a corresponding stimulation of cell cycle progression. The wave 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 in the ISOP + CCl4 group, These findings support the hypothesis that in response to increased infliction of CCl4 injury by isopropanol, augmented stimulation of cell division and tissue repair restrain the progression of injury and restore hepatic structure and function, thereby allowing the rats to survive, Further, antimitotic intervention with colchicine (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 findings suggest that greater stimulation of tissue repair restrains the progression of ISOP-enhanced infliction of CCl4 liver injury and accounts for recovery from enhanced liver injury and animal survival. The findings are consistent with a two-stage model of toxicity wherein liver injury is linked by progression or regression of injury, which is governed by the extent of tissue repair to the final outcome. (C) 1996 Academic Press, Inc.