title: Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury.
abstract: Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively). Thioacetamide pretreatment afforded 100% protection against APAP overdose compared to 100% lethality in the DW + APAP-treated mice. Although hepatic Cyp2e1 was similar at the time of APAP administration, immediate activation of hepatic c-Jun N-terminal kinases (JNK) was observed in the TA + APAP-treated mice compared to its delayed activation in the DW + APAP group. In contrast to the DW + APAP group, the TA + APAP-treated mice exhibited extensive CTR, which was secondary to the timely activation of Wnt/β-catenin pathway. Our data indicate that rapid activation and appropriate termination of Wnt/β-catenin signaling and modulation of JNK activity underlie TA + APAP heteroprotection.
authors.affiliation: Department of Toxicology, College of Health & Pharmaceutical Sciences, The University of Louisiana at Monroe (ULM), Monroe, LA, USA.
authors.forename: Vivekkumar P
authors.initials: VP
authors.lastname: Dadhania
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center (KUMC), Kansas City, KS, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Bhushan
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center (KUMC), Kansas City, KS, USA.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
authors.affiliation: Department of Toxicology, College of Health & Pharmaceutical Sciences, The University of Louisiana at Monroe (ULM), Monroe, LA, USA.
authors.forename: Harihara M
authors.initials: HM
authors.lastname: Mehendale
keywords: Wnt/β-catenin pathway; heteroprotection; liver failure; liver regeneration