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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In early infancy, two unrelated children with Smith-Lemli-Opitz syndrome were found to have elevated levels of androgen sulfates. When the steroid conjugates in the serum of normal infants were hydrolyzed and chromatographed on Sephadex LH-20, 4 androgen containing peaks (I, II, III, IV) were found. In the serum from these two infants with Smith-Lemli-Opitz syndrome, Peaks I and III were increased, but Peaks II and IV were absent. The parents of the two children, and of three additional unrelated children with Smith-Lemli-Opitz syndrome, had exaggerated 17-hydroxyprogesterone responses to an intravenous bolus of ACTH. These findings suggest that a defect in steroid metabolism may be linked to the Smith-Lemli-Opitz syndrome.
Steroids
PMID:Possible abnormalities of steroid secretion in children with Smith-Lemli-Opitz syndrome and their parents. 301 67

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.
Steroids 1996 Sep
PMID:Effect of YM 9429, a potent teratogen, on cholesterol biosynthesis in cultured cells and rat liver microsomes. 888 21

Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome associated with 7-dehydrocholesterol (7DHC) 7-reductase deficiency. Although SLOS can be detected in an affected fetus before midpregnancy by measurement of 7DHC levels in amniotic fluid or chorionic villus cells, a noninvasive, more routine method is needed. Accordingly, this study was instigated to search for specific steroids in maternal urine in an affected pregnancy that reflect the 7-reductase deficiency of the fetus, ie, steroids retaining 7,8-unsaturation. Steroids were characterized by gas chromatography/mass spectrometry after urinary extraction, conjugate separation, and derivatization. Most steroids in maternal urine from a patient carrying a SLOS fetus were identified as progesterone metabolites, and these were entirely conventional, showing no evidence of additional unsaturation. Unsaturated homologues of the cortisol metabolites were also not detected. However, unsaturated homologues of pregnane-3,16,20-triols and pregnane-3,17,20-triol were found. Most likely, these are 7,8-unsaturated homologues, but 8,9-unsaturation is also possible because of the known activity of delta7-delta8-isomerase on 7DHC, which results in 8DHC being a prominent sterol in SLOS. Among these novel human steroids, the following were provisionally characterized: 5beta-pregn-7(or 8)-ene-3alpha,17alpha,20alpha-triol, 5beta-pregn-7(or 8)-ene-3alpha,16alpha,20alpha-triol, and 5alpha-pregn-7(or 8)-ene-3,16alpha,20alpha-triol. Confirmation of the position of unsaturation will require steroid synthesis. These novel steroids are not present in normal pregnancy urine and, therefore, are valuable for prenatal diagnosis of SLOS. In addition, separate studies have shown that 5beta-pregn-7(or 8)-ene-3alpha,17alpha,20alpha-triol is present in urine of children and adults with SLOS, and so is a useful analyte for confirmation of the disorder throughout life.
Steroids 1999 Jul
PMID:Midgestational maternal urine steroid markers of fetal Smith-Lemli-Opitz (SLO) syndrome (7-dehydrocholesterol 7-reductase deficiency). 1044

The biosynthetic abnormality in Smith-Lemli-Opitz syndrome (SLOS) is a deficiency of 7-dehydrocholesterol (7DHC) reductase, the enzyme responsible for catalyzing the final step in the Kandutsch-Russell pathway for cholesterol synthesis. Because the disposition of 7DHC and 8-dehydrocholesterol [8DHC; cholesta-5,8(9)-dien-3beta-ol] produced in this syndrome is little understood, we have analyzed urine from three young infants by gas chromatography/mass spectrometry to characterize its steroid metabolites. All steroid metabolites of adrenal origin found in normal infant urine were also found in urine from the patients with SLOS but in reduced amount. Quantitatively, the major steroids in these SLOS patients were identified by mass spectrometry as homologs of normal neonatal steroids possessing an additional double bond. Generally, two forms of each steroid were present in a similar amount. Because of the markedly increased levels of 7DHC and 8DHC in SLOS, these almost certainly represented the 5,7 and 5,8(9) unsaturated forms of each metabolite. The most abundant steroids were tentatively identified as 3beta,16alpha-dihydroxy-5,7-pregnadien-20-one and 3beta,16alpha-dihydroxy-5,8(9)-pregnadien-20-one, although similar 21-hydroxylated steroids and homologs of 16alpha-hydroxy-DHEA were also found. This study shows that all enzymatic steps used by cholesterol in the DHEA synthetic pathway are also functional for 7DHC and 8DHC.
Steroids 1999 Jul
PMID:Neonatal urinary steroids in Smith-Lemli-Opitz syndrome associated with 7-dehydrocholesterol reductase deficiency. 1044 4

Five unsaturated sterols relevant to the Smith-Lemli-Opitz syndrome have been prepared in high radiochemical purity with a tritium label at the 3alpha position. Swern oxidation of cholesta-5,8-dien-3beta-ol and other unlabeled C27 sterols afforded the corresponding 3-ketosteroids, and reduction with tritiated NaBH4 gave the desired 3alpha-3H sterols, with double bonds at the delta(5,8), delta(5,8(14)), delta(6,8), delta(6,8(14)), and delta8 positions. High radiochemical purity of the tritiated sterols was demonstrated by normal phase, reversed phase, and silver-ion (Ag+) high-performance liquid chromatography (HPLC). In the course of this work, we developed a medium-pressure variant of Ag+-HPLC for purifying radiolabeled samples, documented significant isotopic fractionation of the 3alpha-tritiated sterols and their acetates on Ag+-HPLC, and discovered unexpected effects of a delta(8(14)) bond on the conformation of 3-keto-delta5-steroids. The synthetic and analytical methodologies described herein should provide a sound basis for investigating the origin and metabolism of sterols involved in the Smith-Lemli-Opitz syndrome and in late stages of cholesterol biosynthesis.
Steroids 2000 Jan
PMID:Synthesis of [3alpha-3H]cholesta-5,8-dien-3beta-ol and tritium-labeled forms of other sterols of potential importance in the Smith-Lemli-Optiz syndrome. 1062 34

A wide variety of unsaturated sterols can accumulate in eukaryotic cells as a consequence of normal metabolism, genetic disorders, and actions of enzyme inhibitors. Resolving these sterol mixtures into individual components by conventional chromatographic methods is inefficient because unsaturated sterols differ little in polarity, hydrophobicity, and volatility. Although sterol mixtures are well-resolved by silver-ion high performance liquid chromatography (Ag(+)-HPLC), existing methods require derivatization to acetates for best results, and the isocratic mobile phases lead to long analysis times and low sensitivity for late-eluting sterols. We show that these problems can be overcome with ternary gradient elution using acetone, hexanes, and acetonitrile. Separation of a mixture of 20 underivatized sterols gave dramatically shortened analysis times, with good peak shapes for both early- and late-eluting components. In a similar separation of blood sterols from a patient with Smith-Lemli-Opitz syndrome, the band for 7-dehydrocholesterol was much narrower than with isocratic elution. Column re-equilibration was rapid, and the separations could be monitored with ultraviolet spectroscopy at 210 nm, which affords universal, non-destructive detection of unsaturated sterols. Also discussed are retention mechanisms and reproducibility of Ag(+)-HPLC separations. The overall results represent a major advance in chromatographic methods for resolving mixtures of unsaturated sterols differing in the number and position of olefinic bonds.
Steroids 2002 Oct
PMID:Ternary gradient elution markedly improves silver-ion high performance liquid chromatography of unsaturated sterols. 1223 27

Pregnane-3,17 alpha,20-triols bearing unsaturation at delta(7), delta(8), delta(5,7), or delta(5,8) have been tentatively identified as steroid metabolites in Smith-Lemli-Opitz syndrome (SLOS). Starting with 17 alpha-hydroxypregnenolone diacetate, we have synthesized 13 unsaturated C(21) triols by four different routes in one to four steps. These multifunctional steroids were prepared by a series of regio- and stereoselective transformations chosen to minimize facile olefin isomerization and 17-deoxygenation. The results include a study of stereoselectivity in the reduction of 17 alpha-hydroxy-20-ketosteroids, an alternative method for reducing diethyl azodicarboxylate adducts of delta(5,7) steroids, and an efficient oxidation-isomerization of a delta(5,7) steroid using cholesterol oxidase. The 13 triols and their synthetic precursors were fully characterized by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The NMR data, together with molecular modeling, indicated unanticipated conformational heterogeneity for two synthetic intermediates, 17 alpha-hydroxypregna-4,7-diene-3,20-dione and 17 alpha-hydroxy-5 beta-pregn-7-ene-3,20-dione. The unsaturated C(21) triols are useful as reference standards to study adrenal steroid production in SLOS and to develop methods for pre- and postnatal diagnosis of this congenital disorder.
Steroids 2003 Jan
PMID:Chemical synthesis of 7- and 8-dehydro derivatives of pregnane-3,17alpha,20-triols, potential steroid metabolites in Smith-Lemli-Opitz syndrome. 1247 21

Smith-Lemli-Opitz syndrome (SLOS) is attributable to mutations in the gene coding for 7-dehydrocholesterol reductase. Low to absent enzyme activity accounts for the accumulation of both 7-dehydrocholesterol and 8-dehydrocholesterol in plasma and other tissues. Since oxysterols can participate in the regulation of cholesterol homeostasis, we examined the possibility that they are formed from these dehydrocholesterol intermediates. In patients with SLOS, we found serum levels of 27-hydroxy-7-dehydrocholesterol ranging from 0.1 to 0.25micro M and evidence for circulating levels of 27-hydroxy-8-dehydrocholesterol (0.04-0.51 micro M). Picomolar quantities of 27-hydroxy-7-dehydrocholesterol were identified in normal individuals. Biologic activities of 27-hydroxy-7-dehydrocholesterol were found to include inhibition of sterol synthesis and the activation of nuclear receptor LXRalpha but not that of LXRbeta. These activities occurred at concentrations found in plasma and presumably at those existing in tissues. Thus, patients with SLOS have increased levels of metabolites derived from intermediates in cholesterol synthesis that are biologically active and may contribute to the regulation of cholesterol synthesis in vivo.
Steroids 2003 Aug
PMID:27-Hydroxylation of 7- and 8-dehydrocholesterol in Smith-Lemli-Opitz syndrome: a novel metabolic pathway. 1290 34

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation/mental retardation syndrome with an estimated incidence among individuals of European ancestry of 1 in 20000 to 1 in 30000. It is caused by inactivity of the enzyme 7-dehydrosterol-delta(7)-reductase, which catalyses the terminal transformation in cholesterol synthesis. Patients show not only an increased level of 7-dehydrocholesterol in blood and tissues, but also increased 8-dehydrocholesterol because of the presence of an active delta(8)-delta(7) isomerase. A major consequence of these biochemical abnormalities is the alteration of normal embryonic and fetal somatic development causing postnatal abnormalities of growth, learning, language and behavior. While deficient cholesterol during early development is the primary cause of central nervous system (CNS) abnormalities and retardation, we questioned whether neurosteroids could also be involved since they can have a profound influence on behavioral characteristics. Disordered neurosteroidogenesis would be expected in SLOS and could be caused by a deficiency in classical neurosteroid synthesis secondary to cholesterol deficiency, or by synthesis from 7- and 8-dehydrocholesterol of novel neurosteroids with delta(7) or delta(8) unsaturation which may have altered activity compared with conventional neurosteroids. In particular we sought analogues of dehydroepiandrosterone sulfate, pregnenolone sulfate and the pregnanolone epimers. We targeted urine from post-pubertal females, as this type of sample would be most likely to yield identifiable amounts of the pregnanolone metabolites of progesterone. Analysis by GC/MS of urinary steroids excreted by post-pubertal females confirmed the presence of neurosteroid-like compounds in SLOS patient's urine. Even though the new neuroactive steroids identified were unlikely to have been formed in the brain, it is likely that mechanisms for their synthesis are operable in this organ.
Steroids 2004 Jan
PMID:The implications of 7-dehydrosterol-7-reductase deficiency (Smith-Lemli-Opitz syndrome) to neurosteroid production. 1471 77

Smith-Lemli-Opitz syndrome (SLOS) is caused by deficiency in the terminal step of cholesterol biosynthesis, which is catalyzed by 7-dehydrocholesterol reductase (DHCR7). The disorder exhibits several phenotypic traits including dysmorphia and mental retardation with a broad range of severity. Pathogenesis of SLOS is complex due to multiple roles of cholesterol and may be further complicated by unknown effects of aberrant metabolites that arise when 7-dehydrocholesterol (7-DHC), the substrate for DHCR7, accumulates. A viable mouse model for SLOS has recently been developed, and here we characterize cholesterol metabolism in this model with emphasis on changes during the first few weeks of postnatal development. Cholesterol and 7-DHC were measured in "SLOS" mice and compared with measurements in normal mice. SLOS mice had measurable levels of 7-DHC at all ages tested (up to 1 year), while 7-DHC was below the threshold for detection in normal mice. In perinatal to weaning age SLOS mice, cholesterol and 7-DHC levels changed dramatically. Changes in brain and liver were independent; in brain cholesterol increased several fold while 7-DHC remained relatively constant, but in liver cholesterol first increased then decreased again while 7-DHC first decreased then increased. In older SLOS animals the ratio of 7-DHC/cholesterol, which is an index of biochemical severity, tended to approach, but not reach, normal. While these mice provide the best available genetic animal model for the study of SLOS pathogenesis and treatment, they probably will be most useful at early ages when the metabolic effects of the mutations are most dramatic. To correlate any experimental treatment with improved sterol metabolism will require age-matched controls. Finally, determining the mechanism by which these "SLOS" mice tend to normalize may provide insight into the future development of therapy.
Steroids 2007 Oct
PMID:Cholesterol biosynthesis from birth to adulthood in a mouse model for 7-dehydrosterol reductase deficiency (Smith-Lemli-Opitz syndrome). 1771 50


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