Biomedical subjects

G Salen

Publications and source records attributed to G Salen.

At least 91 records · Page 5Linked to original sources

PubMed1996

Chemical synthesis, structural analysis, and decomposition of N-nitroso bile acid conjugates.

N-nitrosoamides of 7 beta-hydroxylated bile acid conjugates, particularly of the ursodeoxycholic acid family have been synthesized. The products and synthetic intermediates were fully characterized by the results of high-resolution 1H NMR, FT-IR, FABMS and ESI-MS studies. The compounds, N-nitrosoglycoursodeoxycholic acid (NOGUDCA), N-nitrosoglycoursocholic acid (NOGUCA) and N-nitrosoglycodeoxycholic acid (NOGDCA) decomposed between pH 6 and 9 in aqueous buffer solutions, indicating a t1/2 of 5-7 h while N-nitrosotauroursodeoxycholic acid (NOTUDCA) indicated a much longer t1/2 of 15-17 h. These results suggest that the compounds are relatively stable and may enter the enterohepatic circulation. Their decomposition is similar to that of other N-nitrosamides, which generate alkylating agents and thereby act as DNA mutagens.

Bile Acids and Salts↗

PubMed1996

Sitosterolemia: opposing effects of cholestyramine and lovastatin on plasma sterol levels in a homozygous girl and her heterozygous father.

Sitosterolemia is a genetic disorder characterized by sitosterol accumulation in plasma and clinically accelerated atherosclerosis. Under a condition of metabolic control with a 30% fat, low-sitosterol diet, we compared the effects of monotherapy and dual-drug treatment with lovastatin and cholestyramine on plasma sterol parameters and endogenous cholesterol synthesis in a homozygous sitosterolemic patient with concomitant heterozygous familial hypercholesterolemia (FH), her obligate heterozygous father, and hyperlipidemic control subjects. We found that for both the sitosterolemic homozygote and heterozygote, cholestyramine plus lovastatin dual therapy proved not to be superior to either drug treatment alone. In the homozygous patient, cholestyramine accounted for the decrease of plasma sterol (ie, lovastatin was ineffective), whereas in the heterozygote, lovastatin represented the margin of difference (ie, low-dose cholestyramine was relatively ineffective). Thus, the best treatment option for this homozygote child and her heterozygote father appears to be monotherapy with cholestyramine and lovastatin, respectively. Stimulation by bile acid malabsorption produced a dramatic decrease of plasma sterols in the homozygote, without increasing endogenous cholesterol synthesis, but this therapy was ineffective in the heterozygote. Decreasing endogenous cholesterol synthesis with lovastatin was effective in the heterozygote, but ineffective in the homozygote. In suspected sitosterolemia, a poor sterol response to lovastatin and a dramatic response to cholestyramine may differentiate homozygous from heterozygous and other familial forms of hyperlipidemia.

Adult↗

PubMed1996

Effect of YM 9429, a potent teratogen, on cholesterol biosynthesis in cultured cells and rat liver microsomes.

YM 9429 (cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine) is a hypolipidemic agent with a potent and specific teratogenicity, inducing cleft palate and skeletal variations in rats. Since cleft palate is generally observed in the Smith-Lemli-Opitz syndrome, a common syndrome of multiple congenital anomalies caused by reduced activity of 7-dehydrocholesterol delta 7-reductase (3 beta-hydroxysteroid delta 7-reductase), the final enzyme in the cholesterol biosynthetic pathway, YM 9429 was suspected of being an inhibitor of this enzyme. To prove this hypothesis, YM 9429 was added to cultured human skin fibroblasts and to cultured Morris hepatoma cells and incubated with [5-3H]mevalonolactone. After 24 h, radiolabeled 7-dehydrocholesterol accumulated in the cells, whereas the formation of radiolabeled cholesterol was markedly reduced. The results indicate that YM 9429 inhibits the conversion of 7-dehydrocholesterol to cholesterol catalyzed by the microsomal enzyme 7-dehydrocholesterol delta 7-reductase. In rat liver microsomes, the mode of inhibition was found to be noncompetitive, with a Ki of 40 microM. These results suggest that YM 9429 induced developmental abnormalities in rats by the same mechanism as the Smith-Lemli-Opitz syndrome. This compound might be useful for studying the pathogenesis of anomalies in animal models of the Smith-Lemli-Opitz syndrome.

Animals↗

PubMed1996

Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome.

The Smith-Lemli-Opitz syndrome is caused by an inherited defect in 7-dehydrocholesterol-delta7-reductase, the enzyme that catalyzes the last reaction in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. As a result, deficient cholesterol is produced and the precursor 7-dehydrocholesterol and derivatives (8-dehydrocholesterol and 19-nor-5,7,9(10)-cholestatrien-3 beta-ol) accumulate. Tissues (especially brain) deprived of cholesterol, or because of the deposited sterol precursors and derivatives, develop abnormally and function poorly. Replacement with dietary cholesterol may help correct the biochemical defects and improve symptoms.

Adolescent↗

PubMed1996

Measurement of 3 beta-hydroxysteroid delta 7-reductase activity in cultured skin fibroblasts utilizing ergosterol as a substrate: a new method for the diagnosis of the Smith-Lemli-Opitz syndrome.

A new sensitive and specific method for the evaluation of 3 beta-hydroxysteroid delta 7-reductase activity, the defective enzyme in the Smith-Lemli-Opitz (SLO) syndrome, is described. The assay is based on the use of gas chromatography-mass spectrometry with selected-ion monitoring to measure the mass of brassicasterol (ergosta-5,22-dien-3 beta-ol) produced by the incubation of ergosterol (ergosta-5,7,22-trien-3 beta-ol) with cultured human skin fibroblasts. Although the conversion of ergosterol to brassicasterol was slower than the transformation of [3H]7-dehydrocholesterol to [3H] cholesterol, cells from control subjects produced brassicasterol efficiently. In contrast, cells form SLO patients produced very little brassicasterol (P < 0.0001, patients vs. parents or vs. controls). These results indicate that the reduction of ergosterol can be used as an assay for 3 beta-hydroxysteroid delta 7-reductase in human skin fibroblasts, which avoids the many problems caused by the instability and lack of availability of radiolabeled 7-dehydrocholesterol. The present method made it possible to diagnose the SLO syndrome with high sensitivity and reliability using a commercially available compound.

Cholestadienols↗

PubMed1995

Capillary gas-liquid chromatography of 6-hydroxylated bile acids.

Gas-liquid chromatographic separation of several bile acids with a hydroxyl group at C-6 is described on two capillary columns, CP-Sil-19 CB and CP-Sil-5 CB. The gas-liquid chromatographic retention indices of bile acids with 6 alpha- and 6 beta-hydroxyl groups are compared with those of bile acids without the C-6 hydroxyl group and the effect of the C-6 hydroxyl group on the retention indices of bile acids is determined. Both 6 alpha- and 6 beta-hydroxyl groups increase the retention index of a bile acid. The retention indices of 6 alpha- or 6 beta-hydroxyl derivatives of chenodeoxycholic acid were found to be higher than those of the corresponding 6-hydroxy derivatives of cholic acid on the CP-Sil-19 CB column but lower on the CP-Sil-5 CB column. Although all 6-hydroxylated derivatives of lithocholic, chenodeoxycholic and cholic acids were not completely resolved on either column alone, combining the two columns resulted in the complete separation of all these compounds.

Bile Acids and Salts↗

PubMed1995

Prenatal detection of the cholesterol biosynthetic defect in the Smith-Lemli-Opitz syndrome by the analysis of amniotic fluid sterols.

The Smith-Lemli-Opitz (SLO or RSH) syndrome is an autosomal recessive disorder characterized by a recognizable pattern of minor facial anomalies, congenital anomalies of many organs, failure to thrive, and mental retardation. Its cause is a defect in cholesterol biosynthesis characterized by abnormally low plasma cholesterol levels and concentrations of the cholesterol precursor 7-dehydrocholesterol (7DHC) elevated up to several thousand-fold above normal. We used capillary column gas-chromatography to quantify sterols in amniotic fluid, amniotic cells, plasma, placenta, and breast milk from a heterozygous mother who had previously given birth to an affected son and in cord blood and plasma from her affected newborn daughter. The cholesterol concentration in amniotic fluid at 16 weeks gestation was normal, but 7DHC, normally undetectable, was greatly elevated. In cultured amniocytes, the level of 7DHC was 11% of total cholesterol, similar to cultured fibroblasts from patients with SLO syndrome. At 38 weeks, a girl with phenotype consistent with the syndrome was born. Cholesterol concentrations were abnormally low in cord blood and in the baby's plasma at 12 weeks, while levels of 7DHC were grossly elevated, confirming the prenatal diagnosis. The mother's plasma cholesterol increased steadily during gestation but remained below the lower 95% limit reported for normal control women. We conclude that it is now possible to detect the SLO syndrome at 16 weeks gestation by analyzing amniotic fluid sterols.

Amniotic Fluid↗

PubMed1995

Treatment of the cholesterol biosynthetic defect in Smith-Lemli-Opitz syndrome reproduced in rats by BM 15.766.

BACKGROUND & AIMS: The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurological developmental defects and dysmorphic features with a defect in cholesterol synthesis at the conversion of 7-dehydrocholesterol to cholesterol. BM 15.766 inhibits 7-dehydrocholesterol-delta 7-reductase and reproduces the biochemical defect. The aim of this study was to investigate the effects of cholesterol, cholic acid, and lovastatin feeding on rats fed BM 15.766. METHODS: Plasma cholesterol and 7-dehydrocholesterol concentrations were related to the hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. RESULTS: With the inhibitor treatment, plasma cholesterol concentrations decreased 67%; 7-dehydrocholesterol concentrations increased from trace to 17 mg/dL; and hepatic HMG-CoA reductase activity and messenger RNA levels were stimulated 74% and two times, respectively. In inhibitor-treated rats, feeding cholesterol increased plasma cholesterol concentrations 3.7 times, decreased 7-dehydrocholesterol concentrations 88%, and reduced elevated HMG-CoA reductase activity and messenger RNA levels 74% and 49%. Feeding cholic acid increased plasma cholesterol without reducing 7-dehydrocholesterol concentrations. The combination of cholic acid and cholesterol enhanced plasma cholesterol 9.5 times without decreasing 7-dehydrocholesterol levels. Feeding lovastatin depressed plasma cholesterol further without reducing 7-dehydrocholesterol levels. CONCLUSIONS: Cholesterol is essential to correct abnormal cholesterol synthesis induced by BM 15.766 in rats by expanding the pool and inhibiting HMG-CoA reductase. Neither cholic acid nor lovastatin are effective separately, but cholic acid plus cholesterol may offer some additional benefit.

Acyl Coenzyme A↗

PubMed1995

Microwave-induced organic reactions of bile acids: esterification, deformylation and deacetylation using mild reagents.

An efficient and convenient procedure for the esterification, deformylation, and deacetylation of bile acids is described. This is achieved by the addition of a catalytic amount of methanesulfonic acid or para-toluene sulfonic acid to a solution of bile acid in methanol in the domestic microwave oven. All these reactions were completed in the microwave oven within 1-3 min at 60% power (390 W) and the desired bile acids, namely trihydroxy-5 beta-cholestanoic acid, (23R)-3 alpha,7 alpha,23-trihydroxy-5 beta-cholan-24-oic acid, ursocholic acid and 7-ketolithocholic acid were isolated in 86-94% yield.

Acetylation↗

PubMed1995

Regulation of bile acid synthesis by deoxycholic acid in the rat: different effects on cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase.

We examined the effects of feeding deoxycholic acid (1% and 0.4% of diet), alone and in combination with ursodeoxycholic acid, on serum and biliary bile acid concentrations, hepatic morphology, and the activities and steady-state messenger RNA (mRNA) levels of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase in the rat. Feeding 1% deoxycholic acid increased serum bile acid concentrations (cholestasis), produced portal triad inflammation, bile duct proliferation, and severe hepatocyte necrosis with nuclear pleomorphism. Hepatic damage was prevented when ursodeoxycholic acid (1%) was combined with the deoxycholic acid (1%), or when deoxycholic acid intake was reduced to 0.4%. HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities were markedly inhibited (-56% and -55%, respectively) with either 1% or 0.4% deoxycholic acid. Ursodeoxycholic acid alone produced an insignificant decline in HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities, and when combined with 1% deoxycholic acid did not lessen the inhibitory effect of the latter. Steady-state mRNA levels increased 20-fold for HMG-CoA reductase and 53-fold for cholesterol 7 alpha-hydroxylase in rats fed 1% deoxycholic acid. In contrast, 0.4% deoxycholic acid decreased HMG-CoA reductase mRNA levels 76%, and cholesterol 7 alpha-hydroxylase mRNA levels 82%. Ursodeoxycholic acid alone did not affect HMG-CoA reductase or cholesterol 7 alpha-hydroxylase steady-state mRNA levels. Steady-state mRNA levels and activities of sterol 27-hydroxylase, a key enzyme in the alternative acidic pathway of bile acid synthesis, did not change with either high or low doses of deoxycholic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome.

OBJECTIVES: To determine whether type I and the more severe type II variant of Smith-Lemli-Opitz syndrome have the same metabolic defect and to learn which plasma sterol measurements best predict survival. METHODS: Plasma sterols were measured in 33 individuals (24 type I, 9 type II) with a clinical diagnosis of the syndrome. RESULTS: Cholesterol levels were abnormally low (61 +/- 34 mg/dl) in type I subjects, whereas concentrations of the cholesterol precursor 7-dehydrocholesterol and its isomer 8-dehydrocholesterol were elevated 40- to 10,000-fold. Plasma cholesterol levels were significantly lower and total dehydrocholesterol levels higher in type II than in type I. Six children with the type II variant died by 13 weeks with mean plasma cholesterol levels 6.2 +/- 3.1 mg/dl, versus 17 +/- 11 mg/dl in the three surviving children with type II (p < 0.05). No child with a cholesterol level 7 mg/dl or less lived longer than 13 weeks. CONCLUSIONS: Patients with type I and type II variants of Smith-Lemli-Opitz syndrome have markedly reduced activity of the enzyme that converts 7-dehydrocholesterol to cholesterol, but the extent of the block is far more complete in type II. Survival correlates strongly with higher plasma cholesterol concentrations.

Abnormalities, Multiple↗

PubMed1995

Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats.

The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurologic developmental defects and dysmorphic features in many organs. Recently, abnormal cholesterol biosynthesis with impaired conversion of 7-dehydrocholesterol to cholesterol has been discovered in homozygotes. To reproduce the biochemical abnormality, BM 15.766, a competitive inhibitor of 7-dehydrocholesterol-delta 7-reductase, the enzyme that catalyzes the conversion of 7-dehydrocholesterol into cholesterol was fed by gavage to rats. After 14 d, plasma cholesterol concentrations declined from 48 mg/dl to 16 mg/dl and 7-dehydro-cholesterol levels rose from trace to 17 mg/dl. Hepatocytes surrounding the central vein developed balloon necrosis. Stimulating cholesterol synthesis with cholestyramine followed by BM 15.766 produced an additional 40% decline (P < 0.05) in plasma cholesterol and 34% increase in 7-dehydrocholesterol levels compared to the inhibitor alone. Adding 2% cholesterol to the diet during the second week of BM 15.766 treatment increased plasma cholesterol threefold and decreased 7-dehydrocholesterol concentrations 55%. Hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity increased 73% with a 3.9-fold rise in mRNA levels but cholesterol 7 alpha-hydroxylase activity decreased slightly though mRNA levels increased 1.4 times with BM 15.766 treatment. These results demonstrate that BM 15.766 is a potent inhibitor of 7-dehydrocholesterol-delta 7-reductase. The model reproduces abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome and is useful to test different treatment strategies. Stimulating early steps of cholesterol synthesis worsens the biochemical abnormalities while feeding cholesterol inhibits abnormal synthesis, improves the biochemical abnormalities and prevents liver damage.

Abnormalities, Multiple↗

PubMed1995

Unexpected inhibition of cholesterol 7 alpha-hydroxylase by cholesterol in New Zealand white and Watanabe heritable hyperlipidemic rabbits.

We investigated the effect of cholesterol feeding on plasma cholesterol concentrations, hepatic activities and mRNA levels of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase and hepatic LDL receptor function and mRNA levels in 23 New Zealand White (NZW) and 17 Watanabe heritable hyperlipidemic (WHHL) rabbits. Plasma cholesterol concentrations were 9.9 times greater in WHHL than NZW rabbits and rose significantly in both groups when cholesterol was fed. Baseline liver cholesterol levels were 50% higher but rose only 26% in WHHL as compared with 3.6-fold increase with the cholesterol diet in NZW rabbits. In both rabbit groups, hepatic total HMG-CoA reductase activity was similar and declined > 60% without changing enzyme mRNA levels after cholesterol was fed. In NZW rabbits, cholesterol feeding inhibited LDL receptor function but not mRNA levels. As expected, receptor-mediated LDL binding was reduced in WHHL rabbits. Hepatic cholesterol 7 alpha-hydroxylase activity and mRNA levels were 2.8 and 10.4 times greater in NZW than WHHL rabbits. Unexpectedly, cholesterol 7 alpha-hydroxylase activity was reduced 53% and mRNA levels were reduced 79% in NZW rabbits with 2% cholesterol feeding. These results demonstrate that WHHL as compared with NZW rabbits have markedly elevated plasma and higher liver cholesterol concentrations, less hepatic LDL receptor function, and very low hepatic cholesterol 7 alpha-hydroxylase activity and mRNA levels. Feeding cholesterol to NZW rabbits increased plasma and hepatic concentrations greatly, inhibited LDL receptor-mediated binding, and unexpectedly suppressed cholesterol 7 alpha-hydroxylase activity and mRNA to minimum levels similar to WHHL rabbits. Dietary cholesterol accumulates in the plasma of NZW rabbits, and WHHL rabbits are hypercholesterolemic because reduced LDL receptor function is combined with decreased catabolism of cholesterol to bile acids.

Alanine Transaminase↗

PubMed1995

Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes.

We investigated the enzyme defect in late cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome, a recessively inherited developmental disorder characterized by facial dysmorphism, mental retardation, and multiple organ congenital anomalies. Reduced plasma and tissue cholesterol with increased 7-dehydrocholesterol concentrations are biochemical features diagnostic of the inherited enzyme defect. Using isotope incorporation assays, we measured the transformation of the precursors, [3 alpha- 3H]lathosterol and [1,2-3H]7-dehydrocholesterol into cholesterol by liver microsomes from seven controls and four Smith-Lemli-Opitz homozygous subjects. The introduction of the double bond in lathosterol at C-5[6] to form 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120 +/- 8 vs 100 +/- 7 pmol/mg protein per min, P = NS). In distinction, the reduction of the double bond at C-7 [8] in 7-dehydrocholesterol to yield cholesterol catalyzed by 7-dehydrocholesterol-delta 7-reductase was nine times greater in controls than homozygotes microsomes (365 +/- 23 vs 40 +/- 4 pmol/mg protein per min, P < 0.0001). These results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7-dehydrocholesterol as a key intermediate. In Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol. Thus, lathosterol 5-dehydrogenase is equally active which indicates that homozygotes liver microsomes are viable. Accordingly, microsomal 7-dehydrocholesterol-delta 7-reductase is inherited abnormally in Smith-Lemli-Opitz homozygotes.

Cholesterol↗

PubMed1995

Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-Lemli-Opitz syndrome homozygotes.

The Smith-Lemli-Opitz syndrome is a common birth defect syndrome characterized biochemically by low plasma cholesterol levels and high concentrations of the cholesterol precursor 7-dehydrocholesterol. The present study was undertaken to prove that the enzyme defect is at the step in which 7-dehydrocholesterol is converted into cholesterol and to establish a new biochemical method for the diagnosis of this disease. We assayed the latter part of the cholesterol biosynthetic pathway by incubating [3H]lathosterol (the immediate precursor of 7-dehydrocholesterol) with cultured skin fibroblasts from 15 homozygous patients, 14 obligate heterozygous parents, and 8 controls, and measuring its conversion to 7-dehydrocholesterol and cholesterol. The formation of cholesterol from lathosterol in parents was not significantly different from that in controls. In contrast, cells from patients made very little cholesterol (P < 0.0001, patients vs. parents or vs. controls) but readily converted lathosterol to 7-dehydrocholesterol. The defect was especially profound in a subgroup of 8 of the most severely clinically affected patients, as virtually no label was detected in the cholesterol fraction. These results provide compelling evidence that 1) this disease is caused by a primary defect in 7-dehydrocholesterol delta 7-reductase, an essential enzyme in the biosynthesis of cholesterol; 2) the most clinically severe form of the syndrome may be associated with the most inhibited enzyme; and 3) the enzyme lathosterol 5-desaturase that converts lathosterol to 7-dehydrocholesterol is fully intact. The present method using fibroblast and amniocyte cultures establishes it as a useful procedure for the biochemical diagnosis of this syndrome.

Adolescent↗

PubMed1995

Identification of 8-dehydrocholesterol (cholesta-5,8-dien-3 beta-ol) in patients with Smith-Lemli-Opitz syndrome.

Cholesta-5,8-dien-3 beta-ol (8-dehydrocholesterol) and cholesta-5,7-dien-3 beta-ol (7-dehydrocholesterol) were isolated from the fecal neutral sterol fraction from homozygotes with Smith-Lemli-Opitz syndrome. The structures of the sterols were conclusively established from their mass spectra and 1H and 13C nuclear magnetic resonance spectra. It is probable that 8-dehydrocholesterol arises from 7-dehydrocholesterol and is not a direct precursor of cholesterol.

Abnormalities, Multiple↗

PubMed1995

Markedly increased tissue concentrations of 7-dehydrocholesterol combined with low levels of cholesterol are characteristic of the Smith-Lemli-Opitz syndrome.

The Smith-Lemli-Opitz syndrome is an autosomal recessive birth defect (frequency 1:20,000-1:40,000) that results in profound mental retardation, physical deformities, and failure to thrive. It is characterized biochemically by low plasma cholesterol and greatly elevated levels of two dehydrocholesterols, one of which is the cholesterol precursor 7-dehydrocholesterol. To determine whether the block in cholesterol biosynthesis affects tissue sterols, we assayed several organs from two affected individuals, a female who died at 27 hours and a 20-week male fetus. Cholesterol concentrations in abdominal wall, adrenal gland, and kidney from two or three unaffected fetuses, who served as controls, averaged 2.0, 1.5, and 1.4 mg/g wet weight, compared to 0.08, 0.44, and 0.14, respectively, for the homozygous fetus. Cerebral cortex cholesterol concentrations were 2.2 mg/g for two 20-22-week fetal controls but only 0.21 and 0.09 mg/g, respectively, for the homozygous child and fetus. Similarly, tissue cholesterol levels were abnormally low in the homozygous child being less than 1 mg/g in liver, adipose, thymus, muscle, and adrenal and 6.2 mg/dl in plasma. Dehydrocholesterols could not be detected by conventional means in any controls but were elevated enough in tissues from affected individuals to make total sterol concentrations nearly normal. These results suggest that a defect in 3 beta-hydroxysterol delta 7-reductase leads to both a profound lack of cholesterol and its replacement by dehydrocholesterols. Such a combination may be lethal in the most severely affected individuals.

Abnormalities, Multiple↗

PubMed1995

Identification of 19-nor-5,7,9(10)-cholestatrien-3 beta-ol in patients with Smith-Lemli-Opitz syndrome.

We have identified the third unknown sterol in the plasma and tissues of Smith-Lemli-Opitz homozygotes as 19-nor-5,7,9(10)-cholestatrien-3 beta-ol. The structure was established from capillary gas-liquid chromatography retention index and characteristic fragmentation pattern by mass spectrometry that were identical to a synthetic reference standard. Evidence is presented that 19-nor-5,7,9(10)-cholestatrien-3 beta-ol is not an artifact formed during the chemical isolation of the relatively unstable 7-dehydrocholesterol. It is possible that 19-nor-5,7,9(10)-cholestatrien-3 beta-ol may contribute to the clinical abnormalities in patients with Smith-Lemli-Opitz syndrome.

Cholestadienols↗