Membrane Cholesterol Modulates Superwarfarin Toxicity.
Superwarfarins are modified analogs of warfarin with additional lipophilic aromatic rings, up to 100-fold greater potency, and longer biological half-lives. We hypothesized that increased hydrophobicity allowed interactions with amphiphilic membranes and modulation of biological responses. We find that superwarfarins brodifacoum and difenacoum increase lactate production and cell death in neuroblastoma cells. In contrast, neither causes changes in glioma cells that have higher cholesterol content. After choleterol depletion, lactate production was increased and cell viability was reduced. Drug-membrane interactions were examined by surface X-ray scattering using Langmuir monolayers of dipalmitoylphosphatidylcholine and/or cholesterol. Specular X-ray reflectivity data revealed that superwarfarins, but not warfarin, intercalate between dipalmitoylphosphatidylcholine molecules, whereas grazing incidence X-ray diffraction demonstrated changes in lateral crystalline order of the film. Neither agent showed significant interactions with monolayers containing >20% cholesterol. These findings demonstrate an affinity of superwarfarins to biomembranes and suggest that cellular responses to these agents are regulated by cholesterol content.
Department of Anesthesiology, University of Illinois-Chicago, Chicago, Illinois.
M Natalia
MN
Marangoni
Department of Physics and the Center for the Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, Illinois; X-ray Science Division, Argonne National Laboratory, Lemont, Illinois.
Michael W
MW
Martynowycz
X-ray Science Division, Argonne National Laboratory, Lemont, Illinois.
Ivan
I
Kuzmenko
Department of Anesthesiology, University of Illinois-Chicago, Chicago, Illinois.
David
D
Braun
Department of Anesthesiology, University of Illinois-Chicago, Chicago, Illinois.
Paul E
PE
Polak
Department of Anesthesiology, University of Illinois-Chicago, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois.
Guy
G
Weinberg
Jesse Brown VA Medical Center, Chicago, Illinois; Department of Medicine, University of Illinois-Chicago, Chicago, Illinois.
Israel
I
Rubinstein
Department of Physics and the Center for the Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, Illinois.
David
D
Gidalevitz
Department of Anesthesiology, University of Illinois-Chicago, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois. Electronic address: dlfeins@uic.edu.
Douglas L
DL
Feinstein
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D015110:4-Hydroxycoumarins / Q000633:toxicity*; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051381:Rats
D015110:4-Hydroxycoumarins; D015060:1,2-Dipalmitoylphosphatidylcholine; D002784:Cholesterol; C013418:bromfenacoum