Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice. Toxicol Appl Pharmacol 2012 Oct 15;264(2):192-201
Date
08/21/2012Pubmed ID
22902588Pubmed Central ID
PMC3519387DOI
10.1016/j.taap.2012.08.001Scopus ID
2-s2.0-84866841407 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10mg/kg, oral gavage) prior to APAP (200mg/kg IP) and at 7 and 36h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8h, compared to the APAP mice. At 24 and 48h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A(2), and cytosolic and secretory PLA(2) activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E(2) expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE(2) expression and hepatocyte regeneration, likely through a mechanism involving PLA(2).
Author List
Chaudhuri S, McCullough SS, Hennings L, Brown AT, Li SH, Simpson PM, Hinson JA, James LPAuthor
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetaminophenAnalgesics, Non-Narcotic
Animals
Chemical and Drug Induced Liver Injury
Cytokines
Dinoprostone
Hepatocytes
Hypoxia-Inducible Factor 1, alpha Subunit
Immunohistochemistry
Indicators and Reagents
Intercellular Signaling Peptides and Proteins
Liver Regeneration
Male
Mice
Mitochondria, Liver
Permeability
Proliferating Cell Nuclear Antigen
Prostaglandin-Endoperoxide Synthases
Receptors, Phospholipase A2
Signal Transduction
Trifluoperazine
Tumor Necrosis Factor-alpha