Influence of hypotonic stress on the biliary excretion of doxorubicin in Wistar and TR- rats

In tumor cells, doxorubicin (DOX) is excreted by P-glycoprotein (P-gp) and the multidrug resistance-associated protein (mrp). Both transporters might also be involved in cellular regulatory volume decrease (RVD). To study the hepatobiliary excretion of DOX during RVD, isolated livers of Wistar and m ultidrug resistance-associated protein 2 (mrp2)deficient TR- rats were firs t perfused with an isotonic and later with a hypotonic medium. In both rat strains, DOX is effectively excreted into the bile. Within 30 minutes, the biliary excretion of DOX-derived fluorescence steadily increased to 1.1 +/- 0.11 and 0.84 +/-0.05 nmoles/min. g liver in Wistar and TR- rats, respectiv ely. Under hypotonic conditions, DOX excretion followed the biphasic-increa se in bile flow. Excretion was increased to 136 +/- 19% and 176 +/-9% (firs t peak) and to 141 +/- 11% and 157 +/- 14% (second peak) in Wistar and TR- rats, respectively. Our data show that in the liver of both strains, exposu re to a hypotonic medium stimulates DOX excretion, presumably by activation of P-gp and mrp2 during RVD.