The Metabolism of Desmosterol in Human Subjects During Triparanol Administration*

Abstract

Recent studies with triparanol (1-[p-,3-diethylaminoethoxyphenyl ]-1-(p-tolyl) -2-(p-chlorophenyl)ethanol) have demonstrated that this compound inhibits cholesterol biosynthesis by blocking the reduction of 24-dehydrocholesterol (desmosterol) to cholesterol (2-4). Administration of triparanol to laboratory animals and to man results in the accumulation of desmosterol in the plasma and tissues, usually with some concomitant lowering of the plasma total sterol concentration (2, 5). In studies with human subjects it was observed that after about 2 weeks the desmosterol concentration tended to plateau at an average level of 27 per cent of the total circulating sterols (5). The ratios of desmosterol to cholesterol in animal tissues (2) differed somewhat from the ratios in plasma. In addition, injection of the cholesterol precursor 2-C14-mevalonic acid during triparanol administration resulted in the rapid appearance of labeled desmosterol in blood, while no significant radioactivity appeared in cholesterol in the first few days (5).The object of the present experiments was to study the metabolism of desmosterol in patients receiving triparanol. Since cholesterol serves as the biosynthetic precursor for several physiologically important compounds, including bile acids and steroid hormones, the question arose whether desmosterol could also function as a precursor for these compounds without first being transformed into cholesterol. The studies reported herein demonstrate the direct conversion of desmosterol to both bile acids and to steroid hormones, and also provide information about the over-all metabolism of this sterol in the triparanol-treated man. EXPERIMENTALClinical material. Both of the patients studied were hospitalized on a metabolic ward of the Clinical Center.* Presented in part at the First International Pharmacology Meeting, Stockholm, Sweden, August, 1961 (1).Patient G.B. was a 55 year old man with known arteriosclerotic heart disease and mild hypercholesterolemia; since 1957 he had maintained a satisfactory and stable cardiac status. At the time of the present study he had been taking 250 mg triparanol daily for 4 weeks, and had a total serum sterol level in the high normal range. Patient F.A. was a 40 year old man with a 4-to 5-year history of gout and essential hyperlipemia. At the time of this study he had been on an isocaloric low purine diet for several weeks, and both the gout and hyperlipemia were in remission. He received 250 mg triparanol daily for 2 weeks prior to the start of this study.Design of study. Each study was begun in the fasting patient by the rapid injection of 20 /Ac of 2-C14-mevalonic acid, in isotonic saline, into an antecubital vein. Patient F.A. also received, in the same injection, 20 jsc of 7-a H'-cholesterol, previously incorporated into his own serum lipoproteins by the method of Avigan (6). Blood samples were collected 3 hours later from the opposite antecubital vein, and at varying intervals thereafter. We obtained bile in the early mornings by duodenal intubation, em...

The in Vitro Metabolism of Desmosterol With Adrenal and Liver Preparations*

“…In our previous study, indirect evidence was presented for the conversion of desmosterol to bile acids and to steroid hormones in triparanoltreated men (2). The present study provides confirmatory direct evidence for this conclusion by in vitro experiments with tissues from triparanoltreated rats and mice.…”

“…These results confirm our previous in vivo study (2), which suggested that desmosterol was similar to cholesterol in its ability to serve as a precursor for bile acids and for steroid hormones in patients on triparanol therapy.…”

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IN a recent communication (2), it was demonstrated that in human subjects receiving triparanol therapy, 24-dehydrocholesterol (desmosterol) could serve as a direct precursor of several physiologically important compounds normally derived from cholesterol. The results indicated the direct conversion of desmosterol to both bile acids and to steroid hormones in these patients, and suggested that desmosterol was similar to cholesterol in its ability to serve as a precursor for these compoulnds.

The present study compares the metabolism of desmosterol and cholesterol in in vitro adrenal and liver preparations.

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