posted on 2016-02-18, 14:05authored byPriyanka Prakash, Alemayehu A. Gorfe
Prolonged usage of nonsteroidal anti-inflammatory
drugs (NSAIDs)
causes gastrointestinal injury. Bile acids and phospholipids have
been shown to exasperate and attenuate NSAIDs’ toxicity, respectively.
However, the molecular mechanisms underlying these effects remain
undetermined. We have investigated the molecular interactions in various
mixtures of indomethacin (Indo), a commonly used NSAID, and cholic
acid (CA), a bile acid, in the presence and absence of palmitoyloleylphosphatidylcholine
(POPC) lipids. We found that CA and Indo spontaneously form mixed
micelles, with the hydrophobic face of CA and hydrophobic region of
Indo forming the core. Increasing the Indo concentration resulted
in more stable and larger aggregates that contain a progressively
larger number of Indo molecules. More dynamic aggregates with a maximum
size of 15 were obtained when the relative concentration of CA was
higher. The mixture of CA, Indo, and POPC also led to ternary mixed
micelles in which CA and Indo distribute almost uniformly on the surface
such that intra-CA, intra-Indo, and CA/Indo interactions are minimized.
A number of previous reports have shown that Indo perforates the cell
membrane in the presence of bile acids (e.g., Petruzzelli et al.,
(2006) Dig. Dis. Sci., 51, 766–774).
We propose that this may be related to the stable, highly charged,
large CA/Indo binary micelles observed in our simulations. Similarly,
the diminished ability of the CA/Indo mixture to aggregate in the
presence of POPC may partly explain the lower toxicity of PC-conjugated
NSAIDs.