title: Prior administration of a low dose of thioacetamide protects type 1 diabetic rats from subsequent administration of lethal dose of thioacetamide.
abstract: Previously, we reported that an ordinarily non-lethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic rats due to inhibited liver tissue repair, whereas 30 mg TA/kg allows 100% survival due to stimulated although delayed tissue repair. Objective of this investigation was to test whether prior administration of a low dose of TA (30 mg/kg) would lead to sustainable stimulation of liver tissue repair in type 1 diabetic rats sufficient to protect from a subsequently administered lethal dose of TA. Therefore, in the present study, the hypothesis that preplacement of tissue repair by a low dose of TA (30 mg TA/kg, ip) can reverse the hepatotoxicant sensitivity (autoprotection) in type 1 diabetic rats was tested. Preliminary studies revealed that a single intraperitoneal (ip) administration of TA causes 90% mortality in diabetic rats with as low as 75 mg/kg. To establish an autoprotection model in diabetic condition, diabetic rats were treated with 30 mg TA/kg (priming dose). Administration of priming dose stimulated tissue repair that peaked at 72h, at which time these rats were treated with a single ip dose of 75 mg TA/kg. Our results show that tissue repair stimulated by the priming dose enabled diabetic rats to overexpress, calpastatin, endogenous inhibitor of calpain, to inhibit calpain-mediated progression of liver injury induced by the subsequent administration of lethal dose, resulting in 100% survival. Further investigation revealed that protection observed in these rats is not due to decreased bioactivation. These studies underscore the importance of stimulation of tissue repair in the final outcome of liver injury (survival/death) after hepatotoxicant challenge. Furthermore, these results also suggest that it is possible to stimulate tissue repair in diabetics to overcome the enhanced sensitivity of hepatotoxicants.
authors.affiliation: Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Ave, Monroe, LA 71209, USA.
authors.forename: Sachin S
authors.initials: SS
authors.lastname: Devi
authors.forename: Binu K
authors.initials: BK
authors.lastname: Philip
authors.forename: Alan
authors.initials: A
authors.lastname: Warbritton
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: Harihara M
authors.initials: HM
authors.lastname: Mehendale
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology* / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000494:pharmacology* / Q000633:toxicity*; D013936:Thymidine / Q000378:metabolism
chemical_list: D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; D013853:Thioacetamide; D004247:DNA; D019392:Cytochrome P-450 CYP2E1; D013936:Thymidine