BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

Journal Article · Mon Feb 15 00:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.11.017· OSTI ID:21344870

Nagy, Gabor ^[1]; Szarka, Andras ^[2]; Lotz, Gabor ^[3]; Doczi, Judit ^[4]; Wunderlich, Livius ^[1]; Kiss, Andras ^[3]; Jemnitz, Katalin; Veres, Zsuzsa ^[5]; Banhegyi, Gabor ^[1]; Schaff, Zsuzsa ^[3]; Suemegi, Balazs ^[6]; Mandl, Jozsef ^[1]

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1. Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, HAS Pathobiochemistry Research Group, H-1444 Budapest POB 260 (Hungary)
2. Department of Applied Biotechnology and Food Science, Laboratory of Biochemistry and Molecular Biology, Budapest University of Technology and Economics, H-1111 Budapest, Muegyetem rkp. 3. (Hungary)
3. 2nd Department of Pathology, Semmelweis University, H-1091 Budapest, Ulloi ut 93. (Hungary)
4. Department of Medical Biochemistry, Semmelweis University, H-1094 Budapest, Tuzolto u. 37-47. (Hungary)
5. HAS, Chemical Research Center, H-1525 Budapest POB 17 (Hungary)
6. Department of Medical Chemistry, University of Pecs, H-7624 Pecs, Szigeti ut 12. (Hungary)

It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2alpha and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

• OSTI ID: 21344870
• Journal Information: Toxicology and Applied Pharmacology, Vol. 243, Issue 1; Other Information: DOI: 10.1016/j.taap.2009.11.017; PII: S0041-008X(09)00483-9; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
DOSES
ENDOPLASMIC RETICULUM
EOSIN
GLUTATHIONE
HEMATOXYLIN
INJURIES
LIVER
MITOCHONDRIA
PHOSPHORYLATION
STRESSES
TOXICITY
TRANSCRIPTION FACTORS
TRANSLOCATION
AROMATICS
BODY
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CHEMICAL REACTIONS
DIGESTIVE SYSTEM
DISEASES
DRUGS
DYES
GLANDS
HETEROCYCLIC COMPOUNDS
HETEROCYCLIC OXYGEN COMPOUNDS
HYDROXY ACIDS
HYDROXY COMPOUNDS
INDICATORS
ORGANIC ACIDS
ORGANIC BROMINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PEPTIDES
PHENOLS
POLYPEPTIDES
POLYPHENOLS
PROTEINS
PYRANS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS