The influence of pH on the interaction of lipophilic anthracyclines with bovine serum albumin. Quantitative characterization by measurement of fluorescence quenching.
We have investigated the interaction of the lipophilic anthracyclines 4'-iodo-4'-deoxydoxorubicin (IDX) and 4-demethoxy-daunorubicin (DDN) with bovine serum albumin by the quantitation of fluorescence quenching. The protein binding of IDX was extremely sensitive to the pH of the solution in which the complex was formed and paralleled the effect of pH on dimerization of the drug. The effect of pH on the protein binding and self-association of DDN was less extensive. Both compounds exhibited curvilinear Scatchard plots indicating apparent cooperativity in the binding process. Because of the self-association of the drugs in aqueous solution, we attempted to resolve this cooperativity in terms of the preferential binding of the dimer to the acceptor. However, we found that similar Scatchard plots could be simulated by using slightly erroneous estimates of the fluorescence yield of the complex, rendering any such analysis inconclusive. Consequently, the relationship between acceptor concentration and the fraction of ligand bound was considered to be fitted adequately in terms of a single acceptor site per albumin molecule. The pH dependence of the association constants for bovine serum albumin was described best by the hydrophobic interaction of neutral drug monomer with a binding site with titratable affinity. We postulate that the pH-dependent binding of some anthracyclines with albumin may lead to their enhanced uptake, relative to that of non-target organs, into tumours with an acidotic extracellular milieu.
Rivory
L P
LP
University of Queensland, Department of Medicine, Princess Alexandra Hospital, Brisbane, Australia.
Pond
S M
SM
Winzor
D J
DJ
D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D015255:Idarubicin / Q000737:chemistry / Q000378:metabolism*; D008433:Mathematics; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence
D012710:Serum Albumin, Bovine; C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin; D015255:Idarubicin