Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity
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 salinomyc...
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doaj-3f25f7692d6840a180239cc914149d082020-11-25T02:59:47ZengMDPI AGMolecules1420-30492020-03-01255117410.3390/molecules25051174molecules25051174Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its CytotoxicityLidia Radko0Małgorzata Olejnik1Andrzej Posyniak2Department of Pharmacology and Toxicology, National Veterinary Research Institute, 57 Partyzantow Avenue, 24-100 Pulawy, PolandDepartment of Pharmacology and Toxicology, National Veterinary Research Institute, 57 Partyzantow Avenue, 24-100 Pulawy, PolandDepartment of Pharmacology and Toxicology, National Veterinary Research Institute, 57 Partyzantow Avenue, 24-100 Pulawy, PolandSalinomycin 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.https://www.mdpi.com/1420-3049/25/5/1174salinomycincytotoxicitymetabolitesinteractionhumanin vitro |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lidia Radko Małgorzata Olejnik Andrzej Posyniak |
spellingShingle |
Lidia Radko Małgorzata Olejnik Andrzej Posyniak Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity Molecules salinomycin cytotoxicity metabolites interaction human in vitro |
author_facet |
Lidia Radko Małgorzata Olejnik Andrzej Posyniak |
author_sort |
Lidia Radko |
title |
Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity |
title_short |
Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity |
title_full |
Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity |
title_fullStr |
Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity |
title_full_unstemmed |
Primary Human Hepatocytes, But not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity |
title_sort |
primary human hepatocytes, but not hepg2 or balb/c 3t3 cells, efficiently metabolize salinomycin and are resistant to its cytotoxicity |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2020-03-01 |
description |
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. |
topic |
salinomycin cytotoxicity metabolites interaction human in vitro |
url |
https://www.mdpi.com/1420-3049/25/5/1174 |
work_keys_str_mv |
AT lidiaradko primaryhumanhepatocytesbutnothepg2orbalbc3t3cellsefficientlymetabolizesalinomycinandareresistanttoitscytotoxicity AT małgorzataolejnik primaryhumanhepatocytesbutnothepg2orbalbc3t3cellsefficientlymetabolizesalinomycinandareresistanttoitscytotoxicity AT andrzejposyniak primaryhumanhepatocytesbutnothepg2orbalbc3t3cellsefficientlymetabolizesalinomycinandareresistanttoitscytotoxicity |
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