Docosahexaenoic acid reverses cyclosporin A-induced changes in membrane structure and function

The use of a fish oil vehicle for cyclosporin A (CsA) can decrease the toxi c effects of CsA but the mechanism is unclear. Here we examine the mechanis m by which docosahexaenoic acid (DHA), a fish oil-derived polyunsaturated f atty acid, can alter the toxic effects of CsA on mouse organ function, endo thelial macromolecular permeability, and membrane bilayer function. Mice gi ven CsA and fish oil showed increased liver toxicity, kidney toxicity, inco rporation of DHA, and evidence of oxidized fatty acids compared to control animals. We hypothesized that the toxic effects of CsA were primarily a res ult of membrane perturbation, which could be decreased if DHA were not oxid ized. The presence of CsA (10 mol%) alone increased dipalmitoylphosphatidyl choline membrane permeability by seven fold over control (no CsA, no DHA). However, if non-oxidized DHA (15 mol%) and CsA were added to the membrane, the permeability returned to control levels. Interestingly, if the DHA was oxidized, the antagonistic effect of DHA on CsA was completely lost. While CsA alone increased endothelial permeability to albumin, the combination of non-oxidized DHA and CsA had no effect on endothelial macromolecular perme ability. However the combination of oxidized DHA and CsA was no different t han the effects of CsA only. CsA increased the fluorescence anisotropy of D PH in the liquid crystalline state of DPPC, while DHA decreased fluorescenc e anisotropy. However the combination of CsA and DHA was no different than DHA alone. We conclude that non-oxidized DHA can reverse the membrane pertu rbing effects of CsA, and the increases in endothelial macromolecular perme ability, which may explain how fish oil is capable of decreasing the toxici ty of CsA. (C) 2000 Elsevier Science B.V. All rights reserved.