The DOI matches its Crossref record; 211 of the 211 references it cites were found in a registry or an index.
Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity
Open accessAbstract
Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through the formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and, eventually, to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in a collapse of mitochondrial membrane potential and cessation of adenosine triphosphate synthesis. In addition, the release of intermembrane proteins, such as apoptosis-inducing factor and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA fragmentation. Together, these events trigger necrotic cell death. Alternatively, the release of cytochrome c and other proapoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with the formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury.
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1 retracted
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Cited by
Godoy, P., Hewitt, N. J., Albrecht, U., Andersen, M. E., Ansari, N., Bhattacharya, S., Bode, J. G., Bolleyn, J., Borner, C., Böttger, J., et al. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1078-5 · Cited by 1,280
Self-citationDeepTox: toxicity prediction using deep learning
Mayr, A., Klambauer, G., Unterthiner, T., & Hochreiter, S. (2016) · Frontiers in Environmental Science · doi:10.3389/fenvs.2015.00080 · Cited by 1,081
Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update
(2016) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2015.00052 · Cited by 744
Ramachandran, A., McGill, M. R., Xie, Y., Ni, H.-M., Ding, W.-X., & Jaeschke, H. (2013) · Hepatology · doi:10.1002/hep.26547 · Cited by 257
Self-citationFerroptosis is involved in acetaminophen induced cell death
Lőrincz, T., Jemnitz, K., Kardon, T., Mandl, J., & Szarka, A. (2015) · Pathology & Oncology Research · doi:10.1007/s12253-015-9946-3 · Cited by 219
Metadata
- Authors
- Jaeschke, H., McGill, M. R., & Ramachandran, A.
- Venue
- Drug Metabolism Reviews
- Publisher
- Informa UK Limited
- Published
- 2012-01-30
- Volume
- 44
- Issue
- 1
- Pages
- 88-106
- ISSN
- 0360-2532 (ISSN-L)
- 1097-9883
- OpenAlex
- W2074545478
- Cited by
- 964
- References
- 211
- FWCI
- 65.22
- Type
- journal article
- Language
- en
- Open access
- green
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- Jaeschke, H., McGill, M. R., & Ramachandran, A. (2012). Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity. Drug Metabolism Reviews. https://doi.org/10.3109/03602532.2011.602688
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