Effects of Triparanol (Mer-29) on Cholesterol Biosynthesis and on Blood Sterol Levels in Man*

Steinberg, Daniel; Avigan, Joel; Feigelson, Eugene B.

doi:10.1172/jci104323

Cited by 82 publications

(39 citation statements)

References 24 publications

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“…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).…”

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The Metabolism of Desmosterol in Human Subjects During Triparanol Administration*

Goodman¹,

Avigan²,

Wilson³

1962

J. Clin. Invest.

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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...

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The Metabolism of Desmosterol in Human Subjects During Triparanol Administration*

Goodman¹,

Avigan²,

Wilson³

1962

J. Clin. Invest.

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“…The animals with persistent cataracts were sacrificed at 10 months, the controls and those with clearing cataracts when they were 11 months old. In humans, the sterols of metabolically active tissues are in constant equi librium with circulating blood sterols [8] and desmosterol disappears from these tissues within 2 weeks after termination of triparanol treatment [19]. If these observations hold true for rat tissues also, the presence of 10% of lenticular sterols as demosterol up to 12 months after termination of triparanol administration indicates the extremely slow disappearance of desmosterol from the lens.…”

Section: Resultsmentioning

confidence: 97%

“…Triparanol (1-p-tolyl, l-/?-[/9diethylaminoethoxyl]-phenyl, 2-p-chlorophenyl ethanol) has been shown to depress blood cholesterol levels, at least partly, by inhibiting hydrogenation of 24-dehydrocholesterol (desmosterol) [2,19] with resultant accumulation of this sterol in tissues. As an undesirable side effect, cataracts have been observed in patients under triparanol therapy [15,16].…”

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Lipids of the Triparanol Cataract in the Rat

Mizuno¹,

Ellison²,

Chipault³

et al. 1974

Ophthalmic Res

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The lipids of lenses from normal rats have been compared with those from cataractous and clearing lenses from rats fed triparanol. Desmosterol was about 1% of the sterols of normal lenses but amounted to approximately 10% of the sterols in lenses of triparanol-treated rats. Clearing and cataractous lenses contained about the same amount of desmosterol. On a ‘per lens’ basis, and with the exception of sphingomyelin, cataractous lenses contained less phospholipids than control lenses. Clearing lenses were intermediate and showed a tendency to return to normal values. The composition of the phospholipids showed a persistent decrease in phosphatidyl serine in the triparanol-treated animals.

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“…Biochemical analysis revealed that cholesterol was derived from diet or synthesized by human body, so inhibition of cholesterol synthesis was a target to lower cholesterol level without modifying diet. In early studies, Triparanol, which inhibits an enzyme involved in the later stage of cholesterol synthesis, was discovered and introduced into clinical trial [18]. However, because inhibition of the enzyme led to accumulation of its substrate desmosterol and caused severe side effect, Triparanol was withdrawn [19].…”

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Translational research: Lessons from past research, growing up nowadays, and development goal in future

Zhang

Chen

Liu

2011

Sci. China Life Sci.

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Recently, with coming of the "omics" era and rapid development of basic research in biology and medicine, huge information about biology and life has been achieved. However, many research results cannot be translated into clinical practice. Under this circumstance, the concept of "translational research" is raised [1-4] and widely spread. "Translational research" is patient-oriented research which connects basic medicine and clinical medicine [2]. It means more directly and quickly raising questions from clinical practice to basic research and translating findings in basic research into clinical practice. The process of translational research can be summarized as follows: first, according to clinical practice, raising clinical problems and refining scientific questions; then, systematic and in-depth research, which integrates diverse disciplines, including epidemic study, basic research and drug discovery, is carried out; last, through research, the potentially effective strategies or methods for diagnosing, treating or preventing diseases are achieved and translated into clinical practice. Translational research has been developed rapidly in recent years. It is used to direct research in cardiovascular diseases (CVD), cancer, infectious diseases, metabolic diseases, etc.Though the concept "translational research" is relatively new, the bedside-to-bench-to-bedside translational strategy is not original. In the past century, especially in the past several decades, many successful studies were done. These studies contributed to human health greatly and are good examples for translational research. In this review, we will choose to talk several of these studies. We hope that these successful examples in the past will facilitate us to deeply understand translational research in the future. We will talk about research in CVD which achieved great progress in the past.In the mid-20th century, CVD was severe and almost accounted for half of all death in the USA [5]. Framingham Heart Study, an epidemiologic study, was carried out to study CVD in the town of Framingham, Massachusetts in 1948, with 5209 adult healthy subjects enrolled [6]. The detailed information for each subject, including diet, exercise, social relationship, physical examination and medical history, was recorded [6]. The study was implemented for about 20 years at its first stage. After that, the second generation and the third generation of subjects were enrolled in 1971 and in 2002 respectively [7,8]. Up to now, the study has lasted more than 60 years. The results from Framingham Heart Study showed that several factors, including high LDL cholesterol level, cigarette smoking, hypertension, obesity, diabetes, menopause, increased the risk of heart diseases, whereas exercise and high HDL cholesterol decreased the risk of heart diseases. It also showed that the social and physiological factors influenced CVD [9][10][11][12]. In recent years, with the development of technology in genetics, such as GWAS technology, some genetic factors contributing to CVD,...

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Effects of Triparanol (Mer-29) on Cholesterol Biosynthesis and on Blood Sterol Levels in Man*

Cited by 82 publications

References 24 publications

The Metabolism of Desmosterol in Human Subjects During Triparanol Administration*

The Metabolism of Desmosterol in Human Subjects During Triparanol Administration*

Lipids of the Triparanol Cataract in the Rat

Translational research: Lessons from past research, growing up nowadays, and development goal in future

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