Weak polar interactions confer albumin binding site selectivity for haloether anesthetics

Enflurane and isoflurane are structural isomers with different anesthetic potencies and side effects. It is not clear whether these differences are produced by differing occupancy of common protein binding sites or by occupancy of different sites, but the very similar molecular properties make the latter possibility unlikely. In this study, the authors examined binding site selectivity of these anesthetics in human serum albumin (HSA).

Binding of isoflurane and enflurane with HSA was determined with isothermal titration calorimetry. Competition with known ligands (propofol) allowed localization of binding sites within the HSA molecule. Molecular properties of isoflurane and enflurane were calculated.

Isoflurane binds HSA with higher affinity but smaller total enthalpy than enflurane. Enthalpogram analysis suggested that isoflurane bound a single site, whereas enflurane bound two. Competition experiments indicated that enflurane and isoflurane share one binding site, which also binds propofol. The additional enflurane site binds propofol but not isoflurane. Increased salt concentration decreased the affinity for isoflurane but not for enflurane. The dipole moment of isoflurane is higher than that of enflurane, and the isoflurane binding site is more polar.

These data indicate two binding sites of different character for the haloether anesthetics on HSA. One site is more polar and prefers isoflurane, presumably because of its larger dipole. The second site prefers the less polar enflurane. Therefore, weak polar interactions confer considerable selectivity, and differences in drug action may arise from occupancy of different protein sites.