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Am J Physiol Endocrinol Metab 252: E375-E379, 1987;
0193-1849/87 $5.00
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AJP - Endocrinology and Metabolism, Vol 252, Issue 3 E375-E379, Copyright © 1987 by American Physiological Society

ARTICLES

Metabolic basis of diethylaminoethoxyhexestrol-induced phospholipid fatty liver

M. Kubo and K. Y. Hostetler

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.


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