Application of lipid peroxidation products as biomarkers for flutamide-induced oxidative stress in vitro

Teppner, Marieke; Böss, Franziska; Ernst, Beat; Pähler, Axel

doi:10.1016/j.toxlet.2015.08.005

Cited by 12 publications

(4 citation statements)

References 33 publications

(36 reference statements)

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“…Flutamide is an antiandrogenic drug that is completely absorbed from the digestive tract and is usually well tolerated in most patients. Diarrhea occurs in a certain number due to poor tolerability, but its side effects are much more significant, manifested in the form of hepatotoxicity [10].…”

Section: Discussionmentioning

confidence: 99%

Flutamide Induced Liver Injury in Female Patients

Malešević

Bokan

Đajić

2020

EJMED

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Flutamide is the active substance of the drug and belongs to the group of drugs that have antiandrogenic effect. Flutamide prevents the action of male sex hormones, i.e. suppresses the action of testosterone and dihydrotestosterone. Primarily, the indications for the use of flutamide refer to males and the treatment of advanced prostate cancer. It is also used in the treatment of patients with testicles surgically removed, and in patients who have not responded to another type of therapy or do not tolerate other types of treatment. The efficacy of flutamide has also been proven in the treatment of acne, hirsutism and alopecia in men and women with polycystic ovaries. It is important to emphasize that flutamide can cause severe side effects, above all liver damage, so it is not justified to use it in the treatment of conditions other than prostate cancer. Numerous data on hepatotoxicity (retrospective, prospective studies, case reports, surveillance study) were available in literature, which ranged from asymptomatic to acute, fulminant hepatitis that ended in transplantation, i.e. fatal outcome. In our paper, a review of the literature with case reports of notably hepatotoxicity is presented along with a case from our clinical practice.

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Section: Discussionmentioning

confidence: 99%

Flutamide Induced Liver Injury in Female Patients

Malešević

Bokan

Đajić

2020

EJMED

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“…It has been shown that the accumulation of ROS in hepatic cells is an essential step in flutamide hepatotoxicity [ 4 ]. It is implicated that flutamide can promote ROS generation, especially in the mitochondria, by multiple mechanisms [ 10 ]. For instance, flutamide has been shown to inhibit mitochondrial complex I leading to superoxide production through the reduction of molecular oxygen by the NADH/ubiquinone oxidoreductase [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, excessive ROS production can cause mitochondrial damage that may eventually lead to liver diseases [ 9 ]. Emerging evidence implicates that flutamide-induced hepatotoxicity is associated with ROS-mediated oxidative stress [ 10 ]. During the metabolism of flutamide in the liver, it is oxidatively metabolized by microsomal metabolic enzymes and turned into electrophilic metabolites.…”

Section: Introductionmentioning

confidence: 99%

Flutamide Induces Hepatic Cell Death and Mitochondrial Dysfunction via Inhibition of Nrf2-Mediated Heme Oxygenase-1

Zhang

Guo²,

Zhang

et al. 2018

Oxidative Medicine and Cellular Longevity

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Flutamide is a widely used nonsteroidal antiandrogen for prostate cancer therapy, but its clinical application is restricted by the concurrent liver injury. Increasing evidence suggests that flutamide-induced liver injury is associated with oxidative stress, though the precise mechanism is poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor regulating endogenous antioxidants including heme oxygenase-1 (HO-1). This study was designed to delineate the role of Nrf2/HO-1 in flutamide-induced hepatic cell injury. Our results showed that flutamide concentration dependently induced cytotoxicity, hydrogen peroxide accumulation, and mitochondrial dysfunction as indicated by mitochondrial membrane potential loss and ATP depletion. The protein expression of Nrf2 and HO-1 was induced by flutamide at 12.5 μM but was downregulated by higher concentrations of flutamide. Silencing either Nrf2 or HO-1 was found to aggravate flutamide-induced hydrogen peroxide accumulation and mitochondrial dysfunction as well as inhibition of the Nrf2 pathway. Moreover, preinduction of HO-1 by Copp significantly attenuated flutamide-induced oxidative stress and mitochondrial dysfunction, while inhibition of HO-1 by Snpp aggravated these deleterious effects. These findings suggest that flutamide-induced hepatic cell death and mitochondrial dysfunction is assoicated with inhibition of Nrf2-mediated HO-1. Pharmacologic intervention of Nrf2/HO-1 may provide a promising therapeutic approach in flutamide-induced liver injury.

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“…A few proposals have been made regarding possible biomarkers for intracellular level of oxidative stress such as the carbonylation level (aldehydes and ketones) of proteins (Dalle-Donne et al, 2003;Hacişevki et al, 2012;Fernando et al, 2016), the level of oxidized low-density lipoprotein (Itabe, 2012;Osman et al, 2016), oxidized products of lipids such as 4-HNE (4-hydroxynonenal) and MDA (malondialdehyde) (Niki, 2008;Halder and Bhattacharyya, 2014;Teppner et al, 2015), and protein thiols (Giustarini et al, 2012(Giustarini et al, , 2017. There are two general issues with these biomarkers: (1) they tend to reflect the level of oxidation by specific oxidizing molecules; and (2) more importantly, they are not high-throughput, hence it is impractical for large-scale analyses, such as analyses of TCGA tissue samples (https://portal.gdc.cancer.gov/) to elucidate possible causes of specific metabolic changes in such tissues.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Estimation of Oxidative Stress in Cancer Tissue Cells Through Gene Expression Data Analyses

Liu

Cui

2020

Front. Genet.

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Quantitative assessment of the intracellular oxidative stress level is a very important problem since it is the basis for elucidation of the fundamental causes of metabolic changes in diseased human cells, particularly cancer. However, the problem proves to be very challenging to solve in vivo because of the complex nature of the problem. Here a computational method is presented for predicting the quantitative level of the intracellular oxidative stress in cancer tissue cells. The basic premise of the predictor is that the genomic mutation level is strongly associated with the intracellular oxidative stress level. Based on this, a statistical analysis is conducted to identify a set of enzyme-encoding genes, whose combined expression levels can well explain the mutation rates in individual cancer tissues in the TCGA database. We have assessed the validity of the predictor by assessing it against genes that are known to have anti-oxidative functions for specific types of oxidative stressors. Then the applications of the predictor are conducted to illustrate its utility.

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Application of lipid peroxidation products as biomarkers for flutamide-induced oxidative stress in vitro

Cited by 12 publications

References 33 publications

Flutamide Induced Liver Injury in Female Patients

Flutamide Induced Liver Injury in Female Patients

Flutamide Induces Hepatic Cell Death and Mitochondrial Dysfunction via Inhibition of Nrf2-Mediated Heme Oxygenase-1

Quantitative Estimation of Oxidative Stress in Cancer Tissue Cells Through Gene Expression Data Analyses

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