TISSUE-REPAIR RESPONSE AS A FUNCTION OF DOSE IN THIOACETAMIDE HEPATOTOXICITY

The purpose of the present study was to establish a dose-response rela tionship for thioacetamide (TA), where tissue regeneration as well as liver injury were two simultaneous but opposing responses. Male Spragu e-Dawley mts were injected intraperitioneally with a 12-fold dose rang e of TA, and both liver injury and tissue repair were measured. Liver injury was assessed by serum enzyme elevations. Serum alanine aminotra nsferase (ALT) elevation did nor show any dose response over a 12-fold dose range up to 24 hr. A dramatic ALT elevation was evident after 24 hr and only for the highest dose (600 mg/kg). Tissue regeneration res ponse was measured by H-3-thymidine (H-3-T) incorporation into hepatoc ellular DNA and by proliferating cell nuclear antigen (PCNA) procedure during a time course (6, 12, 24, 36, 48, 72, and 96 hr). Tissue regen eration, as indicated by H-3-T incorporation, peaked at 36 hr after ad ministration of a low dose of TA (50 mg/kg). With increasing: doses, a greater but delayed stimulation of cell division was observed until a threshold was reached (300 mg/kg). Above the tissue repair threshold (600 mg/kg), because stimulated tissue repair as revealed by H-3-T inc orporation in hepatonuclear DNA was significantly delayed and attenuat ed injury assessed by serum enzyme elevations was remarkably accelerat ed, indicating unrestrained progression of injury leading to animal de ath. These findings suggest that, in addition to the magnitude of tiss ue repair response, the time at which this occurs is critical in restr aining the progression of injury, thereby determining the ultimate out come of toxicity. Whereas dose-related stimulation of tissue repair le ads to recovery, delayed and diminished tissue repair response at the high dose leads to progression of liver injury, leading to hepatic fai lure and animal death. These findings impact on the concept of employi ng maximally tolerated doses in cancer bioassays. Maximum tolerated do ses might represent maximal stimulation of cell proliferation, thereby enhancing the likelihood of errors in DNA replication. Measuring tiss ue repair and injury is simultaneous biological responses to toxic age nts might increase the usefulness of dose-response paradigms in predic tive toxicology and in risk assessment.