Mitochondria: The gateway for tamoxifen-induced liver injury

Ribeiro, Mariana P.C.; Santos, Ana Lúcia; Custódio, José B.A.

doi:10.1016/j.tox.2014.05.009

Cited by 61 publications

(45 citation statements)

References 94 publications

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“…It was shown that TAM can bind directly to mitochondrial proteins. In particular, it was shown that TAM disrupted mitochondrial functions by mechanism related to alteration of inner mitochondrial membrane fluidity, which in turn affected lipid environment and function of membrane integral proteins, with suppression of 1–5 membrane complexes and impairment of oxidative phosphorylation …”

Section: Resultsmentioning

confidence: 99%

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

Torres-López

Maycotte

Liñán-Rico

et al. 2019

Journal of Leukocyte Biology

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Estrogens demonstrate biological activity in numerous organ systems, including the immune system, and exert their effects through estrogen receptors (ER) of two types: intracellular ERα and ERβ that activate transcriptional factors and membrane G protein‐coupled ER GPER. The latter is capable to mediate fast activation of cytosolic signaling pathways, influencing transcriptional events in response to estrogens. Tamoxifen (TAM), widely used in chemotherapy of ERα‐positive breast cancer, is considered as an ERα antagonist and GPER agonist. TAM was shown to possess “off‐target” cytotoxicity, not related to ER in various tumor types. The present work was designed to study biological effects of TAM on the glucocorticoid (GC)‐resistant cell line Jurkat, derived from acute lymphoblastic leukemia of T lineage (T‐ALL). We have shown that T‐ALL cell lines, in contrast to healthy T cells, express only GPER, but not ERα or ERβ. TAM compromised mitochondrial function and reduced the viability and proliferation of Jurkat cells. Additionally, TAM induced autophagy in a GPER‐dependent manner. Gene expression profiling revealed the up‐regulation of autophagy‐related gene ATG5. Interestingly, TAM sensitized Jurkat cells to dexamethasone (DEX) treatment, which may be related to its capacity to cause autophagy. We suggest that TAM‐based adjuvant therapy may represent a novel strategy in T‐ALL patients handling.

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Section: Resultsmentioning

confidence: 99%

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

Torres-López

Maycotte

Liñán-Rico

et al. 2019

Journal of Leukocyte Biology

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“…When hepatic mitochondrial β-oxidation is inhibited, the accumulated fatty acids are converted to triglycerides, which result in hepatic steatosis 12. Ribeiro et al found that endoxifen has less harmful effects on mitochondria when compared with tamoxifen 28. Therefore, those with the lower levels of endoxifen are more likely to suffer mitochondrial dysfunction and develop fatty liver.…”

Section: Discussionmentioning

confidence: 99%

<em>CYP2D6</em> polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study

Wickramage

Tennekoon

Ariyaratne

et al. 2017

BCTT

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Introduction and aimsTamoxifen is an adjuvant drug effective in treating hormone receptor – positive breast cancer. However, 30%–50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Although association between CYP2D6 polymorphisms and recurrence of breast cancer in patients on tamoxifen had been reported, little evidence exists on association between these polymorphisms and adverse effects to tamoxifen. This study explored the association between CYP2D6 polymorphisms and tamoxifen effects, hitherto not studied in Sri Lanka.MethodsA retrospective preliminary study was carried out on 24 breast cancer patients on tamoxifen for minimally 3 months attending National Cancer Institute, Maharagama, Sri Lanka. They were not on CYP2D6-inhibiting drugs, chemotherapy or other endocrine therapy, and had no conditions that could occur as adverse effects to tamoxifen before starting the therapy. Their blood samples were collected, DNA was extracted and genotyped using SNaPshot Multiplex sequencing based single-nucleotide polymorphism (SNP) assay.ResultsSNP/allele frequencies detected: 1846G>A (confirmatory of *4 null allele)=8.3%; 2549delA (confirmatory of *3 null allele)=50%; 100C>T (suggestive of *10 reduced functional allele, in addition to other alleles)=0%; combination of 2988G>A, −1584C and 2850C>T (strongly suggestive of *41 or other reduced functional allele)=4.8%. Occurrence of heterozygous 2988G>A SNP with −1584C and 2850C>T was significantly higher among those with ultrasound-diagnosed fatty liver following the commencement of tamoxifen therapy (P=0.029). Adverse effects occurred at a significantly higher frequency among postmenopausal women (P=0.041). Three patients who developed recurrence of breast cancer had no association with SNPs tested.ConclusionsCYP2D6 SNP combination 2988G>A, −1584C and 2850C>T, strongly suggestive of *41 reduced functional allele, is likely to be useful in predicting occurrence of adverse effect fatty liver in breast cancer patients on tamoxifen, thereby alternative treatment can be considered and lifestyle modifications implemented. Larger sample studies are recommended with the measurement of tamoxifen and metabolite levels. Alternative therapy should be considered for postmenopausal patients.

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“…Also other researches present evidence that mitochondria are sensitive to the level of cAMP/PKA signaling and can respond by modulating levels of respiratory activity or committing to self-execution, and inhibition of the β -adrenergic receptor/cAMP/PKA axis protects against the oxidant-mediated cell injury [28, 29]. Besides, other researches have shown that benzbromarone could decrease the mitochondrial membrane potential, reduce the enzyme activities in the mitochondria, induce mitochondrial uncoupling, and decrease the adenosine triphosphate (ATP) production, therefore to cause cell apoptosis and necrosis [30, 31]. Some ingredients of Chinese HMs also could induce mitochondrial apoptosis, which could be the underlying mechanism for hepatotoxicity [32].…”

Section: Discussionmentioning

confidence: 99%

To Set Up a Logistic Regression Prediction Model for Hepatotoxicity of Chinese Herbal Medicines Based on Traditional Chinese Medicine Theory

Liu

Chen

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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Aims. To establish a logistic regression (LR) prediction model for hepatotoxicity of Chinese herbal medicines (HMs) based on traditional Chinese medicine (TCM) theory and to provide a statistical basis for predicting hepatotoxicity of HMs. Methods. The correlations of hepatotoxic and nonhepatotoxic Chinese HMs with four properties, five flavors, and channel tropism were analyzed with chi-square test for two-way unordered categorical data. LR prediction model was established and the accuracy of the prediction by this model was evaluated. Results. The hepatotoxic and nonhepatotoxic Chinese HMs were related with four properties (p < 0.05), and the coefficient was 0.178 (p < 0.05); also they were related with five flavors (p < 0.05), and the coefficient was 0.145 (p < 0.05); they were not related with channel tropism (p > 0.05). There were totally 12 variables from four properties and five flavors for the LR. Four variables, warm and neutral of the four properties and pungent and salty of five flavors, were selected to establish the LR prediction model, with the cutoff value being 0.204. Conclusions. Warm and neutral of the four properties and pungent and salty of five flavors were the variables to affect the hepatotoxicity. Based on such results, the established LR prediction model had some predictive power for hepatotoxicity of Chinese HMs.

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Mitochondria: The gateway for tamoxifen-induced liver injury

Cited by 61 publications

References 94 publications

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

<em>CYP2D6</em> polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study

To Set Up a Logistic Regression Prediction Model for Hepatotoxicity of Chinese Herbal Medicines Based on Traditional Chinese Medicine Theory

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