Identification of metabolites of anticancer candidate salinomycin using liquid chromatography coupled with quadrupole time‐of‐flight and hybrid triple quadrupole linear ion trap mass spectrometry

Olejnik, Małgorzata; Radko, Lidia; Jedziniak, Piotr

doi:10.1002/rcm.8082

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…In the in vivo studies, the metabolism of SAL in mice, rat, and chicken was highly efficient with unchanged SAL in excreta representing only 2% of the administered dose [28]. In contrast to normal liver cells, HepG2 hepatoma presented low potency to metabolize SAL, which is comparable to the rat hepatoma (FaO) in our previous study [11,29]. These results confirm again that hepatoma-derived cells lack metabolic activity of CYP enzymes [30].…”

Section: Discussionsupporting

confidence: 64%

Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity

2020

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Salinomycin is a polyether antibiotic showing anticancer activity. There are many reports of its toxicity to animals but little is known about the potential adverse effects in humans. The action of the drug may be connected to its metabolism. That is why we investigated the cytotoxicity of salinomycin and pathways of its biotransformation using human primary hepatocytes, human hepatoma cells (HepG2), and the mouse fibroblast cell line (Balb/c 3T3). The cytotoxicity of salinomycin was time-dependent, concentration-dependent, and cell-dependent with primary hepatocytes being the most resistant. Among the studied models, primary hepatocytes were the only ones to efficiently metabolize salinomycin but even they were saturated at higher concentrations. The main route of biotransformation was monooxygenation leading to the formation of monohydroxysalinomycin, dihydroxysalinomycin, and trihydroxysalinomycin. Tiamulin, which is a known inhibitor of CYP450 izoenzymes, synergistically induced cytotoxicity of salinomycin in all cell types, including non-metabolising fibroblasts. Therefore, the pharmacokinetic interaction cannot fully explain tiamulin impact on salinomycin toxicity.

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Section: Discussionsupporting

confidence: 64%

Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity

2020

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“…In recent years, the group of Olejnik investigated metabolites of SAL intensively. They identified metabolites in tests with human hepatoma cells (HepG2) (14 metabolites) [ 9 ], primary human hepatocytes (PHH) (20 metabolites) [ 10 ], and rat primary hepatocytes (PRH) (16 metabolites) [ 11 ] and rat hepatoma cells (FaO) (three metabolites) [ 11 ]. In contrast, based on the widely usage of SAL as veterinary drug, the degradation behavior including degradation products is well-investigated.…”

Section: Introductionmentioning

confidence: 99%

“…A degradation product with m/z of 531.3 is identified by several studies, and the degradation process is based on C-C cleavage (mainly at the β-hydroxy-ketone position) [12]. [18] Hydroxylation (+O) human hepatoma cells (HepG2) [9] primary human hepatocytes (PHH)…”

Section: Introductionmentioning

confidence: 99%

LC-HRMS-Based Identification of Transformation Products of the Drug Salinomycin Generated by Electrochemistry and Liver Microsome

et al. 2022

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The drug salinomycin (SAL) is a polyether antibiotic and used in veterinary medicine as coccidiostat and growth promoter. Recently, SAL was suggested as a potential anticancer drug. However, transformation products (TPs) resulting from metabolic and environmental degradation of SAL are incompletely known and structural information is missing. In this study, we therefore systematically investigated the formation and identification of SAL derived TPs using electrochemistry (EC) in an electrochemical reactor and rat and human liver microsome incubation (RLM and HLM) as TP generating methods. Liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS) was applied to determine accurate masses in a suspected target analysis to identify TPs and to deduce occurring modification reactions of derived TPs. A total of 14 new, structurally different TPs were found (two EC-TPs, five RLM-TPs, and 11 HLM-TPs). The main modification reactions are decarbonylation for EC-TPs and oxidation (hydroxylation) for RLM/HLM-TPs. Of particular interest are potassium-based TPs identified after liver microsome incubation because these might have been overlooked or declared as oxidated sodium adducts in previous, non-HRMS-based studies due to the small mass difference between K and O + Na of 21 mDa. The MS fragmentation pattern of TPs was used to predict the position of identified modifications in the SAL molecule. The obtained knowledge regarding transformation reactions and novel TPs of SAL will contribute to elucidate SAL-metabolites with regards to structural prediction.

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Cytotoxicity of anticancer candidate salinomycin and identification of its metabolites in rat cell cultures

Radko

Olejnik

2018

Toxicology in Vitro

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Identification of metabolites of anticancer candidate salinomycin using liquid chromatography coupled with quadrupole time‐of‐flight and hybrid triple quadrupole linear ion trap mass spectrometry

Cited by 3 publications

References 20 publications

Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity

Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity

LC-HRMS-Based Identification of Transformation Products of the Drug Salinomycin Generated by Electrochemistry and Liver Microsome

Cytotoxicity of anticancer candidate salinomycin and identification of its metabolites in rat cell cultures

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