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.
Highlights
Acetaminophen (APAP) and popular NSAIDs such as aspirin (ASA), and ibuprofen (IBU) have been used for decreasing inflammation and pain relief for centuries
DLS results showed a slight decrease in the hydrodynamic radius of the vesicles (61.6 ± 0.2 nm, PD 37%) with increasing APAP concentrations in the lipid bilayer (APAP 0.06 wt %: 59.5 ± 0.2 nm, PD 38%, and APAP 0.12 wt %: 60.1 ± 0.3 nm, PD 44%), Table 1
These results indicate an increase in size heterogeneity in the system with an increase in APAP concentration in the vesicles
Summary
Acetaminophen (APAP) and popular NSAIDs (nonsteroidal anti-inflammatory drugs) such as aspirin (ASA), and ibuprofen (IBU) have been used for decreasing inflammation and pain relief for centuries. NSE spectroscopy has been vital to understanding the membrane fluctuations at the length scale of the lipid-bilayer thickness.[33,35,38−41] The dynamic structure factor or the intermediate scattering function, S(Q,t), from NSE can be modeled assuming statistically independent tail-motion, height−height fluctuations (membrane undulations), and translational diffusion (of the entire vesicle)[38]. SANS data were obtained using the NG-7 SANS instrument at the National Institute of Standards and Technology (NIST), NIST Center for Neutron Research (NCNR).[52] The sample-to-detector distances, Lsd, were set to 1, 4, and 13 m, at a neutron wavelength, λ = 6 Å Two background samples (D2O and APAP-saturated D2O) were measured separately and used for background subtraction
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