Mitochondria: the gateway for tamoxifen-induced liver injury
Abstract
Tamoxifen (TAM) is routinely used in the treatment of breast carcinoma. TAM-induced liver injury remains a major concern, as TAM causes hepatic steatosis in a significant number of patients, which can progress toward steatohepatitis. Liver toxicity is generally believed to involve mitochondrial dysfunction and TAM exerts multiple deleterious effects on mitochondria, which may account for the hepatotoxicity observed in patients treated with TAM. Endoxifen (EDX), a key active metabolite of TAM that is being investigated as an alternative to TAM in breast cancer therapy, slightly affects mitochondria in comparison with TAM and this demonstration well correlates with the absence of alterations in the clinical parameters of individuals taking EDX. The steady-state plasma concentrations of TAM and its active metabolites EDX and 4-hydroxytamoxifen (OHTAM) in patients taking TAM are highly variable, reflecting genetic variants of CYP2D6 involved in TAM metabolism. Besides de genetic polymorphisms, the intake of drugs that influence the enzymatic activity of CYP2D6 compromises the therapeutic efficiency of TAM. The knowledge of the impact of the variability of TAM metabolism in the breast cancer treatment explains the discrepant outcomes observed in patients taking TAM, as well as the individual variability of idiosyncratic liver injury and other sides effects observed. Therefore, and contrarily to the clinical use of EDX, the need of therapeutic drug monitoring and a regular assessment of liver function biomarkers should be considered in patients under therapies with TAM. In this review we focus on the mitochondrial effects of TAM and its metabolites and on the role played by mitochondria in the initiating events leading to TAM-induced hepatotoxicity, as well as the clinical implications.
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Acute or sub-chronic exposure to various hepatotoxic compounds, including APAP, tamoxifen, AZT and antidepressants, can cause mitochondrial dysfunction, contributing to liver injury with or without fat accumulation.
“In addition, acute or sub-chronic exposure to various hepatotoxic compounds, including clinically-used drugs, such as acetaminophen (APAP) [18], [19], [20], a major ingredient of Tylenol®, an anti-breast cancer agent tamoxifen [21], an anti-retroviral drug zidovudine (AZT) [22] and antidepressants [23], can cause mitochondrial dysfunction, contributing to”
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Self-citationRibeiro, M. P. C., Santos, A. E., Santos, M. S., et al. (2013) · Life Sciences · doi:10.1016/j.lfs.2013.05.027 · Cited by 6 · see citing works
Self-citationSilva, F. S. G., Ribeiro, M. P. C., Santos, M. S., Rocha‐Pereira, P., Santos‐Silva, A., & Custódio, J. B. A. (2013) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-013-9517-9 · Cited by 5 · see citing works
Self-citationMODULATORY EFFECTS OF L-CARNITINE ON TAMOXIFEN TOXICITY AND ONCOLYTIC ACTIVITY: IN VIVO STUDY
Ibrahim, A. B. (2012) · Al-Azhar Journal of Pharmaceutical Sciences/Al-Azhar Journal of Pharmaceutical Sciences · doi:10.21608/ajps.2012.7152 · Cited by 3 · see citing works
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Hutchison, A. L., Tavaglione, F., Romeo, S., & Charlton, M. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.08.030 · Cited by 250 · see citing works
Song, B.-J., Akbar, M., Abdelmegeed, M. A., Byun, K., Lee, B., Yoon, S. K., & Hardwick, J. P. (2014) · Redox Biology · doi:10.1016/j.redox.2014.10.004 · Cited by 123 · see citing works
“In addition, acute or sub-chronic exposure to various hepatotoxic compounds, including clinically-used drugs, such as acetaminophen (APAP) [18–20], a major ingredient of Tylenol, an anti-breast cancer agent tamoxifen [21], an anti-retroviral drug zidovudine (AZT) [22] and antidepressants [23], can cause mitochondrial…”
BackgroundBakadlag, R., Limniatis, G., Georges, G., & Georges, E. (2023) · BMC Cancer · doi:10.1186/s12885-022-10474-x · Cited by 9 · see citing works
- Authors
- Ribeiro, M. P. C., Santos, A. E., & Custódio, J. B. A.
- Affiliations
- Centro de Neurociências e Biologia Celular (PT)
- Corresponding author
- Custódio, José B.A.
- Venue
- Toxicology
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 323
- Pages
- 10-18
- ISSN
- 0300-483X (ISSN-L)
- OpenAlex
- W2000542914
- Cited by
- 70
- References
- 103
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 12 · 2022: 7 · 2021: 9 · 2020: 2 · 2019: 7 · 2018: 5 · 2017: 8 · 2016: 4 · 2015: 4 · 2014: 2
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Portuguese Foundation for Science and Technology (FCT) (SFRH/BD/65130/2009)
- Center for Neuroscience and Cell Biology, University of Coimbra, Portugal (PEst-C/SAU/LA0001/2013-2014)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- tamoxifen, hepatotoxicity, mitochondrial dysfunction, endoxifen, 4-hydroxytamoxifen, CYP2D6 polymorphism, drug metabolism, hepatic steatosis, steatohepatitis, breast cancer treatment, therapeutic drug monitoring, liver function biomarkers, idiosyncratic liver injury
- MeSH terms
- Animals, Humans, Mitochondria, Liver, Tamoxifen, Antineoplastic Agents, Hormonal, Chemical and Drug Induced Liver Injury
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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