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

Filipa S. Carvalho, Catarina M. Morais, Jon M Holy, Dmytro Krasutsky, Sergiy V Yemets, Pavel A. Krasutsky, Amália S. Jurado, Paulo J. Oliveira, Teresa L. Serafim

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)198-210
Number of pages13
JournalChemico-Biological Interactions
Volume296
DOIs
StatePublished - Dec 25 2018

Bibliographical note

Funding Information:
This work is funded by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and national funds by FCT -Foundation for Science and Technology under projects POCI-01-0145-FEDER-007440 , POCI-01-0145-FEDER-016659 , PTDC/DTP-FTO/2433/2014 . T.L.S. supported by the FCT postdoctoral fellowship SFRH/BPD/75959/2011 and C.M.M. supported by the FCT doctoral fellowship SFRH/BD/79077/2011 both co-financed by POPH - Programa Operacional Potencial Humano, QREN and European Union .

Funding Information:
This work is funded by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and national funds by FCT -Foundation for Science and Technology under projects POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-016659, PTDC/DTP-FTO/2433/2014. T.L.S. supported by the FCT postdoctoral fellowship SFRH/BPD/75959/2011 and C.M.M. supported by the FCT doctoral fellowship SFRH/BD/79077/2011 both co-financed by POPH- Programa Operacional Potencial Humano, QREN and European Union.

Keywords

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

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