Showing papers on "Steroid biosynthesis published in 1999"

Neurosteroids: Expression of Steroidogenic Enzymes and Regulation of Steroid Biosynthesis in the Central Nervous System

Abstract: Steroid hormones, which are synthesized in the adrenal gland, gonads and placenta, exert a large array of biological effects on the nervous system. In particular, steroid hormones play an important role in the development, growth, maturation, and differentiation of the central nervous system (CNS)2

Pancreatic solid-cystic-papillary tumor: clinicopathologic features in eight patients from Hong Kong and review of the literature.

Abstract: Solid-cystic-papillary tumors (SCPTs) of the pancreas are rare. The clinicopathologic features and pathogenesis of these tumors have attracted a number of investigations, but the results remain unclear. We investigated the clinicopathologic data, immunohistochemical expression of the pan-endocrine markers, hormones, steroid receptors, and p53 overexpression in pancreatic SCPTs from eight Chinese patients (seven women, one man) collected over a 24-year period. They accounted for 2.5% of the primary pancreatic tumors. The tumors were seen in young women (mean age 27 years). They were large (mean size of resected tumor was 8.4 cm), benign, had solid and cystic areas, and were evenly distributed in the pancreas. The main differential diagnosis was pancreatic endocrine tumor. The tumors were negative for pan-endocrine markers, hormones, estrogen receptor, progesterone receptor, and p53. To date, 452 pancreatic SCPTs have been documented in the English literature. They occurred in patients of different ethnic groups, particularly in non-Caucasians. The tumors were frequently noted in young females. Uncommon cases of malignant pancreatic SCPTs were often found in older men and had indolent behavior. It was concluded that pancreatic SCPTs have distinct clinicopathologic characteristics. The present observations, together with a review of the literature suggests that overexpression of p53 or estrogen receptor is not important in the pathogenesis of pancreatic SCPTs.

Steroid hormone receptors: evolution, ligands, and molecular basis of biologic function.

Abstract: The characterization of the superfamily of nuclear receptors, in particular the steroid/retinoid/thyroid hormone receptors, has resulted in a more complete understanding of how a repertoire of hormonally and nutritionally derived lipophilic ligands controls cell functions to effect development and homeostasis. As transducers of hormonal signaling in the nucleus, this superfamily of DNA-binding proteins appears to represent a crucial link in the emergence of multicellular organisms. Because nuclear receptors bind and are conformationally activated by a chemically diverse array of ligands, yet are closely related in general structure, they present an intriguing example of paralogous evolution. It is hypothesized that an ancient prototype receptor evolved into an intricate set of dimerizing isoforms, capable of recognizing an ensemble of hormone-responsive element motifs in DNA, and exerting ligand-directed combinatorial control of gene expression. The effector domains of nuclear receptors mediate transcriptional activation by recruiting coregulatory multisubunit complexes that remodel chromatin, target the initiation site, and stabilize the RNA polymerase II machinery for repeated rounds of transcription of the regulated gene. Because some nuclear receptors also function in gene repression, while others are constitutive activators, this superfamily of proteins provides a number of avenues for investigating hormonal regulation of gene expression. This review surveys briefly the latest findings in the nuclear receptor field and identifies particular areas where future studies should be fruitful. J. Cell. Biochem. Suppls. 32/33:110-122, 1999.

Paracrine glucocorticoid activity produced by mouse thymic epithelial cells

Abstract: Previous data have suggested that glucocorticoids (GCs) are involved in the differentiation of thymocytes into mature T cells. In this report we demonstrate that the mouse thymic epithelial cells (TEC) express the cytochrome P450 hydroxylases Cyp11A1, Cyp21, and Cyp11B1. These enzymes, in combination with 3beta-hydroxysteroid dehydrogenase (3betaHSD), convert cholesterol into corticosterone, the major GC in rodents. In addition, when TEC were cocultured with 'reporter cells' containing the glucocorticoid receptor (GR) and a GR-dependent reporter gene, a specific induction of reporter gene activity was observed. Induction of reporter gene activity was blocked when the TEC and reporter cells were incubated in the presence of the Cyp11B1 inhibitor metyrapone or the 3betaHSD inhibitor trilostane, as well as by the GR antagonist RU486. Coculturing of TEC with thymocytes induced apoptosis in the latter, which was partially blocked by the enzyme inhibitors and RU486. We conclude that TEC secrete a GC hormone activity and suggest a paracrine role for this in thymocyte development.

Peripheral-Type Benzodiazepine Receptor

Abstract: Eukaryotic steroid hormones, derived from cholesterol, are involved in the maintenance of the organism’s homeostasis, adaptability to the environment, and developmental and reproductive functions. In addition to the well-defined actions in peripheral tissues, steroids have pleiotropic actions on the central nervous system (CNS), where they control a number of neuroendocrine and behavioral functions. Thus, comprehension of the molecular systems underlying the control of steroid hormone biosynthesis is essential for the study and treatment of a multitude of physiological disorders.

Fertility and Infertility: Genetic Contributions from the Hypothalamic-Pituitary- Gonadal Axis

Abstract: Infertility affects approximately 1 in 10 couples. Causes include physical, environmental, and genetic factors, and both partners are equally likely to be affected. It is often difficult to establish a diagnosis for the cause of infertility. “Idiopathic infertility” still predominates as a diagnosis, which reflects the challenges of defining the pathophysiology of infertility in individual couples. Nevertheless, treatment is often successful, using ovulation induction, in vitro fertilization, or ICSI (intracytoplasmic sperm injection). Given the large number of genes that are potentially involved in sex determination, steroidogenesis, and fertility, space limitations preclude a comprehensive review of all genetic abnormalities associated with infertility (e.g. chromosomal abnormalities, disorders of steroid biosynthesis, and metabolic disorders). In this review, we have focused primarily on genes involved in the hypothalamic-pituitary-gonadal (HPG) axis. These disorders have provided important insight into the function of the reproductive axis in humans and may point the way toward improved strategies for the diagnosis and treatment of infertility. Several single-gene disorders affect HPG function and fertility in humans (Fig. 1 and Table 1). Although most of these disorders are relatively rare, they should be considered as causes of infertility for a variety of reasons. First, understanding the pathophysiology of infertility can allow patients to be counseled about their prognosis and the risk of transmitting a condition to their children. Second, treatment can be tailored more appropriately in the context of known hormonal deficits. Finally, it is likely that the cases described to date represent the most severe end of the phenotypic spectrum. Disorders associated with milder phenotypes may be more common and could provide further information about the transcription factors, hormones, and receptors involved in reproduction.

Expression of 17beta-hydroxysteroid dehydrogenase types 1, 2, 3 and 4 in the human temporal lobe

Abstract: Sex steroid hormones exert important biological effects on the brain. Moreover, an extensive sex steroid metabolism occurs in the brain. In sex steroid metabolism 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play essential roles in catalyzing the final steps in androgen and estrogen biosynthesis. Recently four types of human 17beta-HSDs and a pseudogene of the type 1 isoform were identified. To date, 17beta-HSD has not been extensively studied in the human brain. Therefore, we investigated the mRNA expression of the four isozymes of 17beta-HSD as well as the pseudogene of the type 1 isoform in the human temporal lobe to determine the predominant isoforms and, moreover, to elucidate the existence of possible sex and age differences. We studied biopsy materials from the temporal lobe of 34 women, 32 men and 10 children. Quantification of different mRNAs was achieved by competitive reverse transcription-PCR. 17beta-HSD 1, 17beta-HSD 3 and 17beta-HSD 4 were expressed in the human temporal lobe of children and adults, whereas 17beta-HSD 2 and the pseudogene of 17beta-HSD 1 were not expressed. In adults, 17beta-HSD 3 and 17beta-HSD 4 mRNA concentrations were significantly higher in the subcortical white matter (17beta-HSD 3: 14 591+/-3457 arbitrary units (aU), mean+/-s.e.m.; 17beta-HSD 4: 1201+/-212 aU) than in the cortex (17beta-HSD 3: 5428+/-1057 aU, P<0. 0002; 17beta-HSD 4: 675+/-74 aU, P<0.004). 17beta-HSD 1 concentrations did not differ significantly between the white matter (3860+/-1628 aU) and the cortex (2525+/-398 aU) of adults. In conclusion, the present study demonstrates the expression of 17beta-HSD 1, 3 and 4 mRNAs in the human temporal lobe. Together with CYP19AROM and 5alpha-reductase, known to be expressed in the human brain, the expression of 17beta-HSD 1, 3 and 4 mRNAs indicates the major importance of local steroid biosynthesis in the brain.

The role of arachidonic acid on LH-stimulated steroidogenesis and steroidogenic acute regulatory protein accumulation in MA-10 mouse Leydig tumor cells.

Abstract: Metabolic pathways leading to the production of arachidonic acid (AA) and its metabolites have been reported to have modulatory effects on steroidogenesis in a number of cell types. To examine the importance of the arachidonic acid pathway in steroid production and steroidogenic acute regulatory (StAR) protein expression, luteinizing hormones (LH) or N 6-2-o-dibutyryl-adenosine-3∶5-cyclic monophosphate-(Bt2cAMP) stimulated MA-10 mouse Leydig tumor cells were treated with various concentrations of quinacrine (an inhibitor of arachidonic acid production). Incubation of the cells with quinacrine resulted in dose-dependent decreases in steroid production and StAR protein. Twenty micromolars quinacrine inhibited 92 and 91% of LH-induced progesterone and StAR protein, respectively, and 98 and 90% of Bt2cAMP-induced progesterone and StAR protein. Reversal of this inhibition was obtained by incubation of quinacrine-treated cells with various levels of AA, which resulted in a dose-dependent increase in both steroid and StAR protein levels. Two hundred micromolars of AA rescued 57 and 60% of the LH-induced steroid production and StAR protein, respectively, and 52 and 89% of Bt2cAMP-induced steroid production and StAR protein. These results suggest that the effect of AA on LH- and cAMP-stimulated steroidogenesis is associated with the modulation of StAR protein expression.

Synthesis of steroids in pancreas: evidence of cytochrome P-450scc activity.

Abstract: In pancreas, the activities of several sex steroid-transforming enzymes have been reported. Data have been obtained in perfused organs, total tissue homogenates, and subcellular organelles. These data, concurrent with the description of the presence of ligand-regulated steroid receptors, as well as the sexually dimorphic behavior of some pancreatic tumors, are clear evidence in support of the participation of steroid hormones in the pancreatic function. In this study, the steroidogenic ability of the pancreas was demonstrated by two different methods: (a) in tissue homogenates, by the identification of cytochrome P-450scc gene (CYP11A) transcripts after reverse transcription-polymerase chain reaction amplification (RT-PCR); and (b) in isolated mitochondria by the glutethimide-dependent inhibition of cholesterol-pregnenolone biotransformation. The results obtained in a series of independent experiments showed that (a) the pancreatic tissue possessed transcriptional activity of the CYPIIA gene, although to a lesser extent than the typical steroidogenic tissues, and (b) isolated mitochondria obtained from the pancreas were able consistently to synthesize pregnenolone; furthermore, the addition of the specific inhibitor aminoglutethimide (AMG) blocked its synthesis. On the whole, these findings are interpreted as clear evidences of the activity of the cytochrome P-450scc enzymatic complex (P450scc), responsible for the transformation of cholesterol into pregnenolone and considered the first and limiting step in steroid biosynthesis.

Mercuric Triflate and Olefin Cyclization

Abstract: During a trip to Indonesia, I came across a tropical fruit, duku. By extraction of the fruit skin, a hair growth active triterpene lansic acid (1) was isolated. In our planned total synthesis of 1, an effective olefin cyclization agent was required, and mercuric triflate (2) was bone. Then we carried out syntheses of a variety of polycyclic terpenoids and investigated the mechanism of biomimetic olefin cyclization. Upon cyclization of geranylgeranyl acetate, we detected chair/boat/chair cyclization products along with chair/chair/chair cyclization in 1 : 5 ratio. On the basis of the observation that the mercuric triflate is stable but still reactive enough in the presence of water, we trapped each cationic intermediate with water by cyclization in aqueous media. This is the first experimental evidence of the stepwise mechanism of olefin cyclization that takes place via conformationally flexible cationic intermediates. In this review we also deal with an approach into the mystery of the steroid biosynthesis, and a synthetic study toward the taxane skeleton by means of mercuric triflate-induced olefin cyclization.

What is the origin of 3-methylglutaconic acid?

Abstract: Increased urinary excretion of 3-methylglutaconic acid (3-MGC) and to a lesser extent 3-methylglutaric acid (3-MGR) is a not uncommon finding in children who are being investigated for presumed inborn errors of metabolism. During the last 5 years we have identified 70 such individuals. None of these had the characteristic clinical and laboratory findings of the three well-defined syndromes of 3-methylglutaconic aciduria (types I, II and III); all therefore were classified as type IV, the 'unspecified form' of Sweetman and Williams (1995). The origin of 3-MGC and its reduced metabolite 3-MGR in type IV methylglutaconic aciduria is not known (nor indeed is it for types II and III). The only proven enzymatic defect is in type I, the rarest of the four types, where 3-methylglutaconyl-CoA hydratase, an enzyme of the leucine catabolic pathway, is deficient. It has been suggested that 3-MGC (and thus 3-MGR) could occur as by-products of steroid synthesis (Kelley et al 1991) via the so-called mevalonate shunt pathway. Although the results of initial investigations of steroid biosynthesis in methylglutaconic aciduria were not promising (Ibel et al 1993), support was lent to this hypothesis by our finding that increased excretion of 3-MGC and 3-MGR was a normal finding during pregnancy when an increased flux through steroid biosynthesis would be expected (Walsh et al 1997). To further test this hypothesis, we examined urine specimens from patients with congenital adrenal hyperplasia (CAH), who would also be expected to have increased flux through the steroid biosynthetic pathways when under suboptimal control.

Molecular Genetics of Hypertension

Abstract: 1. Hypertension as a Complex Trait Amenable to Genetic Analysis: Basic Strategies and Integrative Approaches. 2. Improved Strategies for the Mapping of Quantitative Trait Loci in the Rat Model. 3. Genetic and Cogenic Mapping of Loci for Blood Pressure and Blood Pressure-related phenotypes in the Rat. 4. Molecular Genetics of Steroid Biosynthesis in Dahl Salt-Sensitive and Salt-resistant Rats: Linkage to the Control of Blood Pressure. 5. Transgenic Rats and Hypertension. 6. Mutating Genes to Study Hypertension. 7. Monogenic Forms of Mineralocoticoid Hypertension. 8. Teh Amiloride-sensitive Epithelial Na+ Channel: Structure and Function of a Key Molecule for Salt Homeostasis. 9. The Study of Candidate Genes in Hypertension Using Tools of Molecular Biology and Genetic Epidemiology. 10. Angiotensinogen and Hypertension. 11. Pharmacogenomics in Arterial Hypertension. 12. Molecular Genetics of Hypertension: Future Directions and Impact on Clinical Management.

DNA encoding peripheral-type benzodiazipine receptor associated protein 7 and applications or methods of use

Abstract: The present invention relates to nucleic acids encoding peripheral-type benzodiazepine receptor (PBR)-associated proteins (PAPs), and nucleic acids that hybridize or are variant of nucleic acids encoding the peripheral-type benzodiazepine receptor (PBR)-associated proteins (PAPs), which are capable of encoding proteins that regulate the function of PBRs affecting both steroid biosynthesis and mediating cholesterol delivery as well as other PBR-mediated functions.