  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
DOPC, a commonly found phospholipid in mammalian cell membranes to synthesize
large unilamellar vesicles to investigate how the incorporation of APAP changes
pure lipid vesicle structure, morphology, and fluidity at different
concentrations. We used a combination of dynamic light scattering (DLS),
small-angle neutron and X-ray scattering (SANS, SAXS), cryo TEM for structural
characterization, and neutron spin-echo (NSE) spectroscopy to investigate
dynamics. We showed that the incorporation of Acetaminophen in the lipid
bilayer significantly impacts the spherical phospholipid self-assembly in terms
of its morphology as well as influences the lipid content in the bilayer,
causing a decrease in bending rigidity. We discussed how the overall impact of
APAP molecules on the pure lipid membrane may play a significant role in the
drug's mechanisms of action. Our results showed the incorporation of APAP
reduces membrane rigidity as well as changes the spherical unilamellar vesicles
into much more irregularly shaped vesicles. Although 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
was also observed. rigidity. A strong effect on the lipid tail motion was also
observed.
