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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Lidia RadkoAndrzej Posyniak

Abstract

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.

References

Feb 1, 1985·Toxicology Letters·E Borenfreund, J A Puerner
Nov 25, 1983·Journal of Immunological Methods·C Korzeniewski, D M Callewaert
Mar 12, 2004·Chemico-biological Interactions·Gyula SzucsKatalin Monostory
Jan 11, 2011·Toxicology and Applied Pharmacology·J L C M DorneJ Fink-Gremmels
Jun 3, 2011·Cell Death & Disease·W Boehmerle, M Endres
Oct 16, 2012·Bioorganic & Medicinal Chemistry Letters·Adam Huczyński
Feb 16, 2013·Toxicology Letters·A ScherzedN Kleinsasser
Jan 24, 2014·Expert Opinion on Drug Metabolism & Toxicology·Petra MatoulkováJiří Vlček
Nov 28, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Michał AntoszczakAdam Huczyński
Dec 17, 2014·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Wojciech CybulskiWojciech Rzeski
Feb 13, 2018·Journal of Experimental & Clinical Cancer Research : CR·Jiang JiangZeyao Tang
Jul 18, 2018·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Lidia Radko, Małgorzata Olejnik
Jan 26, 2017·EFSA Journal·UNKNOWN EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP)Jürgen Gropp

❮ Previous
Next ❯

Software Mentioned

LightSight
Prism5
GraphPad Prism
Multiquant
GraphPad

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.