Diethylaminoethoxyhexestrol caused a foam cell
lipidosis in humans characterized by
phospholipid storage in the liver, spleen, and other tissues, and this represents the first description of acquired
lipidosis caused by a
drug. It has been proposed that
diethylaminoethoxyhexestrol causes
phospholipid fatty liver by concentrating in lysosomes and inhibiting
phospholipases but it has not previously been possible to measure the intralysosomal concentration of
diethylaminoethoxyhexestrol. In this paper we report for the first time the intralysosomal concentration of this
drug in rats. After a single oral dose of
diethylaminoethoxyhexestrol (100 mg/kg) the intralysosomal concentration was 7.9 mM at 2.5 h, 15.6 mM at 12 h, and 20.9 mM at 24 h, respectively. The total
phospholipid content of lysosomes in
drug-treated rats increased 1.9-, 6.0-, and 7.6-fold over control at 2.5, 12, and 24 h, respectively. Purified lysosomal
phospholipase A1 was strongly inhibited by
diethylaminoethoxyhexestrol in vitro. In
phospholipid fatty liver,
phospholipid accumulation in lysosomes appears to be caused by the presence of
diethylaminoethoxyhexestrol in lysosomes at concentrations estimated to be 7.9-20 mM, because
drug levels above 1 mM completely block the activity of purified lysosomal
phospholipase A1 in vitro.