Tissue repair response as a function of dose in thioacetamide hepatotoxicity.
The purpose of the present study was to establish a dose-response relationship for thioacetamide (TA), where tissue regeneration as well as liver injury were two simultaneous but opposing responses. Male Sprague-Dawley rats were injected intraperitioneally with a 12-fold dose range of TA, and both liver injury and tissue repair were measured. Liver injury was assessed by serum enzyme elevations. Serum alanine aminotransferase (ALT) elevation did not 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 response was measured by 3H-thymidine (3H-T) incorporation into hepatocellular DNA and by proliferating cell nuclear antigen (PCNA) procedure during a time course (6, 12, 24, 36, 48, 72, and 96 hr). Tissue regeneration, as indicated by 3H-T incorporation, peaked at 36 hr after administration 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 3H-T incorporation in hepatonuclear DNA was significantly delayed and attenuated, injury assessed by serum enzyme elevations was remarkably accelerated, indicating unrestrained progression of injury leading to animal death. These findings suggest that, in addition to the magnitude of tissue repair response, the time at which this occurs is critical in restraining the progression of injury, thereby determining the ultimate outcome of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Mangipudy
R S
RS
Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209-0470, USA.
Chanda
S
S
Mehendale
H M
HM
D000410:Alanine Transaminase / Q000097:blood*; D000818:Animals; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D009336:Necrosis / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase; D013853:Thioacetamide / Q000008:administration & dosage* / Q000633:toxicity; D013997:Time Factors
D013853:Thioacetamide; D004247:DNA; D000410:Alanine Transaminase