Acetaminophen Interactions with Phospholipid Vesicles Induced Changes in Morphology and Lipid Dynamics

Judith U. De Mel; Sudipta Gupta; Sydney Harmon; Laura Stingaciu; Eric W. Roth; Miriam Siebenbuerger; Markus Bleuel; Gerald J. Schneider

doi:10.1021/acs.langmuir.1c01458

Acetaminophen Interactions with Phospholipid Vesicles Induced Changes in Morphology and Lipid Dynamics

Judith U. De Mel, Sudipta Gupta, Sydney Harmon, Laura Stingaciu, Eric W. Roth, Miriam Siebenbuerger, Markus Bleuel, Gerald J. Schneider

SANS & Spin Echo

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Acetaminophen (APAP) or paracetamol, despite its wide and common use for pain and fever symptoms, shows a variety of side effects, toxic effects, and overdose effects. The most common form of toxic effects of APAP is in the liver where phosphatidylcholine is the major component of the cell membrane with additional associated functionalities. Although this is the case, the effects of APAP on pure phospholipid membranes have been largely ignored. Here, we used 1,2-di-(octadecenoyl)-sn-glycero-3-phosphocholine (DOPC), a commonly found phospholipid in mammalian cell membranes, to synthesize large unilamellar vesicles to investigate how the incorporation of APAP changes the pure lipid vesicle structure, morphology, and fluidity at different concentrations. We used a combination of dynamic light scattering, small-angle neutron and X-ray scattering (SANS, SAXS), and cryo-TEM for structural characterization, and neutron spin-echo (NSE) spectroscopy to investigate the dynamics. We showed that the incorporation of APAP in the lipid bilayer significantly impacts the spherical phospholipid self-assembly in terms of its morphology and influences the lipid content in the bilayer, causing a decrease in bending rigidity. We observe a decrease in the number of lipids per vesicle by almost 28% (0.06 wt % APAP) and 19% (0.12 wt % APAP) compared to the pure DOPC (0 wt % APAP). Our results showed that the incorporation of APAP reduces the membrane rigidity by almost 50% and changes the spherical unilamellar vesicles into much more irregularly shaped vesicles. Although the bilayer structure did not show much change when observed by SAXS, NSE and cryo-TEM results showed the lipid dynamics change with the addition of APAP in the bilayer, which causes the overall decreased membrane rigidity. A strong effect on the lipid tail motion showed that the space explored by the lipid tails increases by a factor of 1.45 (for 0.06 wt % APAP) and 1.75 (for 0.12 wt % APAP) compared to DOPC without the drug.

Original language	English
Pages (from-to)	9560-9570
Number of pages	11
Journal	Langmuir
Volume	37
Issue number	31
DOIs	https://doi.org/10.1021/acs.langmuir.1c01458
State	Published - Aug 10 2021

Funding

The neutron scattering work is supported by the U.S. Department of Energy (DOE) under EPSCoR grant no. DE-SC0012432 with additional support from the Louisiana Board of Regents. This work made use of the BioCryo facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the IIN, and Northwestern’s MRSEC program (NSF DMR-1720139). Access to the neutron spin echo spectrometer and small-angle scattering instruments was provided by the Center for High-Resolution Neutron Scattering, a partnership between the National Institute of Standards and Technology and the National Science Foundation under agreement no. DMR-1508249. The authors acknowledge support from J. Krzywon for experiments at NG-7 SANS beamline. Research conducted at the Spallation Neutron Source (SNS) at Oak Ridge National Laboratory (ORNL) was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. DOE. The authors acknowledge Thomas Weiss from BL 4-2 at Stanford Synchrotron Radiation Lightsource for assisting with SAXS experiments (SSRL proposal no. 5195). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. SAXS data used in this publication were collected at the Small Angle X-ray Scattering (SAXS) beamline at the Center for Advanced Microstructures and Devices (CAMD). The authors thank Jibao He at Tulane University for assisting with preliminary cryo-TEM experiments. S.H. acknowledges financial support by the REU NSF CHE1660009.

Funders	Funder number
REU NSF	CHE1660009
SHyNE Resource	ECCS-2025633, NSF DMR-1720139
Scientific User Facilities Division
National Science Foundation	DMR-1508249
National Institutes of Health
U.S. Department of Energy
National Institute of General Medical Sciences	P41GM103393
National Institute of Standards and Technology
Office of Experimental Program to Stimulate Competitive Research	DE-SC0012432
Office of Science	DE-AC02-76SF00515
Basic Energy Sciences
Biological and Environmental Research
Oak Ridge National Laboratory
Louisiana Board of Regents

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title = "Acetaminophen Interactions with Phospholipid Vesicles Induced Changes in Morphology and Lipid Dynamics",

abstract = "Acetaminophen (APAP) or paracetamol, despite its wide and common use for pain and fever symptoms, shows a variety of side effects, toxic effects, and overdose effects. The most common form of toxic effects of APAP is in the liver where phosphatidylcholine is the major component of the cell membrane with additional associated functionalities. Although this is the case, the effects of APAP on pure phospholipid membranes have been largely ignored. Here, we used 1,2-di-(octadecenoyl)-sn-glycero-3-phosphocholine (DOPC), a commonly found phospholipid in mammalian cell membranes, to synthesize large unilamellar vesicles to investigate how the incorporation of APAP changes the pure lipid vesicle structure, morphology, and fluidity at different concentrations. We used a combination of dynamic light scattering, small-angle neutron and X-ray scattering (SANS, SAXS), and cryo-TEM for structural characterization, and neutron spin-echo (NSE) spectroscopy to investigate the dynamics. We showed that the incorporation of APAP in the lipid bilayer significantly impacts the spherical phospholipid self-assembly in terms of its morphology and influences the lipid content in the bilayer, causing a decrease in bending rigidity. We observe a decrease in the number of lipids per vesicle by almost 28% (0.06 wt % APAP) and 19% (0.12 wt % APAP) compared to the pure DOPC (0 wt % APAP). Our results showed that the incorporation of APAP reduces the membrane rigidity by almost 50% and changes the spherical unilamellar vesicles into much more irregularly shaped vesicles. Although the bilayer structure did not show much change when observed by SAXS, NSE and cryo-TEM results showed the lipid dynamics change with the addition of APAP in the bilayer, which causes the overall decreased membrane rigidity. A strong effect on the lipid tail motion showed that the space explored by the lipid tails increases by a factor of 1.45 (for 0.06 wt % APAP) and 1.75 (for 0.12 wt % APAP) compared to DOPC without the drug.",

author = "{De Mel}, {Judith U.} and Sudipta Gupta and Sydney Harmon and Laura Stingaciu and Roth, {Eric W.} and Miriam Siebenbuerger and Markus Bleuel and Schneider, {Gerald J.}",

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doi = "10.1021/acs.langmuir.1c01458",

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T1 - Acetaminophen Interactions with Phospholipid Vesicles Induced Changes in Morphology and Lipid Dynamics

AU - De Mel, Judith U.

AU - Gupta, Sudipta

AU - Harmon, Sydney

AU - Stingaciu, Laura

AU - Roth, Eric W.

AU - Siebenbuerger, Miriam

AU - Bleuel, Markus

AU - Schneider, Gerald J.

PY - 2021/8/10

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N2 - Acetaminophen (APAP) or paracetamol, despite its wide and common use for pain and fever symptoms, shows a variety of side effects, toxic effects, and overdose effects. The most common form of toxic effects of APAP is in the liver where phosphatidylcholine is the major component of the cell membrane with additional associated functionalities. Although this is the case, the effects of APAP on pure phospholipid membranes have been largely ignored. Here, we used 1,2-di-(octadecenoyl)-sn-glycero-3-phosphocholine (DOPC), a commonly found phospholipid in mammalian cell membranes, to synthesize large unilamellar vesicles to investigate how the incorporation of APAP changes the pure lipid vesicle structure, morphology, and fluidity at different concentrations. We used a combination of dynamic light scattering, small-angle neutron and X-ray scattering (SANS, SAXS), and cryo-TEM for structural characterization, and neutron spin-echo (NSE) spectroscopy to investigate the dynamics. We showed that the incorporation of APAP in the lipid bilayer significantly impacts the spherical phospholipid self-assembly in terms of its morphology and influences the lipid content in the bilayer, causing a decrease in bending rigidity. We observe a decrease in the number of lipids per vesicle by almost 28% (0.06 wt % APAP) and 19% (0.12 wt % APAP) compared to the pure DOPC (0 wt % APAP). Our results showed that the incorporation of APAP reduces the membrane rigidity by almost 50% and changes the spherical unilamellar vesicles into much more irregularly shaped vesicles. Although the bilayer structure did not show much change when observed by SAXS, NSE and cryo-TEM results showed the lipid dynamics change with the addition of APAP in the bilayer, which causes the overall decreased membrane rigidity. A strong effect on the lipid tail motion showed that the space explored by the lipid tails increases by a factor of 1.45 (for 0.06 wt % APAP) and 1.75 (for 0.12 wt % APAP) compared to DOPC without the drug.

AB - Acetaminophen (APAP) or paracetamol, despite its wide and common use for pain and fever symptoms, shows a variety of side effects, toxic effects, and overdose effects. The most common form of toxic effects of APAP is in the liver where phosphatidylcholine is the major component of the cell membrane with additional associated functionalities. Although this is the case, the effects of APAP on pure phospholipid membranes have been largely ignored. Here, we used 1,2-di-(octadecenoyl)-sn-glycero-3-phosphocholine (DOPC), a commonly found phospholipid in mammalian cell membranes, to synthesize large unilamellar vesicles to investigate how the incorporation of APAP changes the pure lipid vesicle structure, morphology, and fluidity at different concentrations. We used a combination of dynamic light scattering, small-angle neutron and X-ray scattering (SANS, SAXS), and cryo-TEM for structural characterization, and neutron spin-echo (NSE) spectroscopy to investigate the dynamics. We showed that the incorporation of APAP in the lipid bilayer significantly impacts the spherical phospholipid self-assembly in terms of its morphology and influences the lipid content in the bilayer, causing a decrease in bending rigidity. We observe a decrease in the number of lipids per vesicle by almost 28% (0.06 wt % APAP) and 19% (0.12 wt % APAP) compared to the pure DOPC (0 wt % APAP). Our results showed that the incorporation of APAP reduces the membrane rigidity by almost 50% and changes the spherical unilamellar vesicles into much more irregularly shaped vesicles. Although the bilayer structure did not show much change when observed by SAXS, NSE and cryo-TEM results showed the lipid dynamics change with the addition of APAP in the bilayer, which causes the overall decreased membrane rigidity. A strong effect on the lipid tail motion showed that the space explored by the lipid tails increases by a factor of 1.45 (for 0.06 wt % APAP) and 1.75 (for 0.12 wt % APAP) compared to DOPC without the drug.

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Acetaminophen Interactions with Phospholipid Vesicles Induced Changes in Morphology and Lipid Dynamics

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