Triton WR-1339, a lysosomotropic compound, is excreted into bile and alters the biliary excretion of lysosomal enzymes and lipids

Abstract

In these experiments, we tested two hypothesis: first, that Triton WR-1339, a nonionic detergent which is sequestered in hepatocyte lysosomes, undergoes biliary excretion; and second, that Triton WR-1339, which also alters serum lipid levels and modifies hepatic catabolism of lipoproteins, affects the biliary output of proteins and lipids. When 3H-Triton WR-1339 was administered to rats, biochemical and morphologic studies showed that hepatocyte lysosomes sequestered Triton WR-1339: (i) the subcellular distribution of 3H was identical to that of lysosomal enzymes after liver fractionation by differential or isopycnic centrifugation, and (ii) lysosomes appeared engorged with Triton WR-1339 on electron microscopy. 3H was also excreted into bile in parallel to three lysosomal enzymes. Triton WR-1339 administration caused a coordinate increase in the biliary excretion of three lysosomal enzymes and also increased the biliary output of total protein, bile acids, and phospholipid. Triton WR-1339 administration did not affect bile flow or the biliary outputs of cholesterol, plasma membrane, and cytosolic enzymes, but did decrease biliary cholesterol saturation by 50%. These results demonstrate that an exogenous compound which is sequestered in hepatocyte lysosomes may be excreted directly into bile in parallel with endogenous lysosomal constituents. The data also show that such a lysosomotropic agent may also selectively modify the biliary excretion of proteins and lipids. The findings are consistent with the existence of a lysosome-to-bile hepatic excretory pathway and suggest that hepatocyte lysosomes may be important in modulating biliary protein and lipid secretion.