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Chem Biol Interact. 2018 Dec 25;296:198-210. doi: 10.1016/j.cbi.2018.10.002. Epub 2018 Oct 4.

Toxicity of lupane derivatives on anionic membrane models, isolated rat mitochondria and selected human cell lines: Role of terminal alkyl chains.

Author information

1
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, Portugal; Department of Life Sciences, University of Coimbra, Portugal.
2
Department of Biomedical Sciences, University of Minnesota Medical School, USA.
3
University of Minnesota Duluth, Natural Resources Research Institute, USA.
4
Department of Life Sciences, University of Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
5
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, Portugal.
6
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, Portugal. Electronic address: tserafim@medicina.ulisboa.pt.

Abstract

Triterpenoids have multiple biological properties, although little information is available regarding their toxicity. The present study evaluates the toxicity of two new synthetic lupane derivatives using distinct biological models including synthetic lipids membranes, isolated liver and heart mitochondria fractions, and cell lines in culture. The two novel triterpenoids caused perturbations in the organization of synthetic lipid bilayers, leading to changes in membrane fluidity. Inhibition of cell proliferation and mitochondrial and nuclear morphological alterations were also identified. Inhibition of mitochondrial oxygen consumption, transmembrane electric potential depolarization and induction of the mitochondrial permeability transition pore was observed, although effects on isolated mitochondrial fractions were tissue-dependent (e.g. liver vs. heart). The size and length of hydrocarbon chains in the two molecules appear to be determinant for the degree of interaction with mitochondria, especially in the whole cell environment, where more barriers for diffusion exist. The results suggest that the positively charged triterpenoids target mitochondria and disrupt bioenergetics.

KEYWORDS:

Betulin; Dihydrobetulin; Lupane; Membrane fluidity; Mitochondrial toxicity; Quaternary ammonium compound; Triterpenoid

PMID:
30292691
DOI:
10.1016/j.cbi.2018.10.002
[Indexed for MEDLINE]

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