title: Enhanced hepatotoxicity and toxic outcome of thioacetamide in streptozotocin-induced diabetic rats.
abstract: Diabetes is known to potentiate thioacetamide (TA)-induced liver injury via enhanced bioactivation. Little attention has been given to the role of compensatory tissue repair on ultimate outcome of hepatic injury in diabetes. The objective of this study was to investigate the effect of diabetes on TA-induced liver injury and lethality and to investigate the underlying mechanisms. We hypothesized that hepatotoxicity of TA in diabetic rats would increase due to enhanced bioactivation-mediated liver injury and also due to compromised compensatory tissue repair, consequently making a nonlethal dose of TA lethal. On day 0, male Sprague-Dawley rats (250-300 g) were injected with streptozotocin (STZ, 60 mg/kg ip) to induce diabetes. On day 10 the STZ-induced diabetic rats and the nondiabetic rats received a single dose of TA (300 mg/kg ip). This normally nonlethal dose of TA caused 90% mortality in the STZ-induced diabetic rats. At various times (0-60 h) after TA administration, liver injury was assessed by plasma alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH), and liver histopathology. Liver function was evaluated by plasma bilirubin. Cell proliferation and tissue repair were evaluated by [(3)H]thymidine ((3)H-T) incorporation and proliferating cell nuclear antigen (PCNA) assays. In the nondiabetic rat, liver necrosis peaked at 24 h and declined thereafter toward normal by 60 h. In the STZ-induced diabetic rat, however, liver necrosis was significantly increased from 12 h onward and progressed, culminating in liver failure and death. Liver tissue repair studies showed that, in the liver of nondiabetic rats, S-phase DNA synthesis was increased at 36 h and peaked at 48 h following TA administration. However, DNA synthesis was approximately 50% inhibited in the liver of diabetic rats. PCNA study showed a corresponding decrease of cell-cycle progression, indicating that the compensatory tissue repair was sluggish in the diabetic rats. Further investigation of tissue repair by employing equitoxic doses (300 mg TA/kg in the non-diabetic rats; 30 mg TA/kg in the diabetic rats) revealed that, despite equal injury up to 24 h following injection, the tissue repair response in the diabetic rats was much delayed. The compromised tissue repair prolonged liver injury in the diabetic rats. These studies suggest that the increased TA hepatotoxicity in the diabetic rat is due to combined effects of increased bioactivation-mediated liver injury of TA and compromised compensatory tissue repair.
authors.affiliation: Department of Toxicology, The University of Louisiana at Monroe, Monroe, Louisiana 71209, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: R D
authors.initials: RD
authors.lastname: Fontenot
authors.forename: M G
authors.initials: MG
authors.lastname: Soni
authors.forename: T J
authors.initials: TJ
authors.lastname: Bucci
authors.forename: H M
authors.initials: HM
authors.lastname: Mehendale
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000473:pathology; D004247:DNA / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000473:pathology; D004357:Drug Synergism; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D009336:Necrosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013853:Thioacetamide / Q000633:toxicity*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D013853:Thioacetamide; D004247:DNA; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D001663:Bilirubin; D013936:Thymidine