Van Luu-The

Laval University, Québec, Quebec, Canada

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Publications (275)936.99 Total impact

  • Van Luu-The
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    ABSTRACT: There is some confusion in the literature about steroidogenesis in endocrine glands and steroidogenesis in peripheral intracrine tissues. The objective of the present review is to bring some clarifications and better understanding about steroidogenesis in these two types of tissues. Concerns about substrate specificity, kinetic constants and place of enzymes in the pathway have been discussed. The role of 17α-hydroxylase/17-20 lyase (CYP17A1) in the production of dehydroepiandrosterone and back-door pathways of dihydrotestosterone biosynthesis is also analyzed.
    The Journal of steroid biochemistry and molecular biology 06/2013; · 2.66 Impact Factor
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    ABSTRACT: The sulfated neurosteroids pregnenolone sulfate (Δ(5)PS) and dehydroepiandrosterone sulfate (DHEAS) are known to play a role in the control of reproductive behavior. In the frog Pelophylax ridibundus, the enzyme hydroxysteroid sulfotransferase (HST), responsible for the biosynthesis of Δ(5)PS and DHEAS, is expressed in the magnocellular nucleus (Mgd) and the anterior preoptic area (Poa), two hypothalamic regions that are richly innervated by GnRH1-containing fibers. This observation suggests that GnRH1 may regulate the formation of sulfated neurosteroids to control sexual activity. Double-labeling of frog brain slices with HST and GnRH1 antibodies revealed that GnRH1-immunoreactive fibers are located in close vicinity of HST-positive neurons. The cDNAs encoding three GnRH receptors (designated riGnRHR-1, -2, and -3) were cloned from the frog brain. Reverse transcription-polymerase chain reaction analyses revealed that riGnRHR-1 is strongly expressed in the hypothalamus and the pituitary while riGnRHR-2 and -3 are primarily expressed in the brain. In situ hybridization histochemistry indicated that GnRHR-1 and GnRHR-3 mRNAs are particularly abundant in Poa and Mgd whereas the concentration of GnRHR-2 mRNA in these two nuclei is much lower. Pulse-chase experiments using tritiated Δ(5)P and DHEA as steroid precursors, and 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as a sulfonate moiety donor, showed that GnRH1 stimulates in a dose-dependent manner the biosynthesis of Δ(5)PS and DHEAS in frog diencephalic explants. Since Δ(5)PS and DHEAS, like GnRH, stimulate sexual activity, our data strongly suggest that some of the behavioral effects of GnRH could be mediated via the modulation of sulfated neurosteroid production.
    Endocrinology 04/2013; · 4.72 Impact Factor
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    ABSTRACT: Abstract Objective: To examine maternal insulin resistance in relationship with maternal and fetal androgen levels as well as with term placenta mRNA and protein abundance of steroidogenic enzymes implicated in androgen dynamics. Methods: The study included 20 women with gestational diabetes mellitus and 27 controls tested using a 120 min., 75g oral glucose tolerance test. Maternal and fetal plasma concentrations of total testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) were measured by high-performance gas chromatography and chemical ionization mass spectrometry at 26.1±3.7 weeks of pregnancy. Results: Glycemic response to oral glucose over 120 min. as well as Matsuda insulin sensitivity and HOMA insulin resistance (HOMA-IR) indices were significantly associated with testosterone levels (r=0.31, r=-0.37 and r=0.35 respectively, p≤0.05 for all). Among male offspring, a positive association between maternal and fetal testosterone levels was observed (r=0.43, p≤0.05). Testosterone levels were higher in the cord blood of newborns from insulin resistant mothers compared to newborns from insulin sensitive mothers (0.48±0.36 nmol/L vs. 0.29±0.18 nmol/L p≤0.05). No difference was observed in mRNA abundance or protein expression of placental steroidogenic enzymes according to the degree of maternal insulin resistance. Conclusion: Our results demonstrate a possible association between fetal and maternal androgen concentrations in relationship with insulin resistance.
    The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 10/2012; · 1.36 Impact Factor
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    ABSTRACT: Novel agents for the endocrine therapy of breast cancer are needed, especially in order to take advantage of the multiple consecutive responses observed in metastatic progressing breast cancer following previous hormone therapy, thus delaying the use of cytotoxic chemotherapy with its frequent poor tolerance and serious side effects. Acolbifene (ACOL) is a novel and unique antiestrogen which represents a unique opportunity to achieve the most potent and specific blockade of estrogen action in the mammary gland and uterus while exerting estrogen-like beneficial effects in other tissues, especially the bones. To better understand the specificity of action of ACOL, we have used Affymetrix GeneChips containing 45,000 probe sets to analyze 34,000 genes to determine the specificity of this compound compared to the pure antiestrogen fulvestrant, as well as to the mixed antagonists/agonists tamoxifen and raloxifene to block the effect of estradiol (E(2)) and to induce effects of their own on the genomic profile in the mouse mammary gland. The genes modulated by E(2) were those identified in two separate experiments and validated by quantitative real-time PCR (qPCR). Three hours after the single subcutaneous injection of E(2) (0.05 μg), the simultaneous administration of ACOL, fulvestrant, tamoxifen, and raloxifene blocked by 98, 61, 43, and 92 % the number of E(2)-upregulated genes, respectively. On the other hand, 70, 10, 25, and 55 % of the genes down-regulated by E(2) were blocked by the same compounds. Of the 128 genes modulated by E(2), 49 are associated with tumorigenesis while 22 are known to be associated with breast cancer. When used alone, ACOL modulated the smallest number of genes also influenced by E(2), namely 4 %, thus possibly explaining potential utilities of this compound in breast cancer prevention and therapy.
    Breast Cancer Research and Treatment 06/2012; 134(2):625-47. · 4.47 Impact Factor
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    ABSTRACT: Adipogenesis and lipid storage in human adipose tissue are inhibited by androgens such as DHT. Inactivation of DHT to 3α-diol is stimulated by glucocorticoids in human preadipocytes. We sought to characterize glucocorticoid-induced androgen inactivation in human preadipocytes and to establish its role in the antiadipogenic action of DHT. Subcutaneous and omental primary preadipocyte cultures were established from fat samples obtained in subjects undergoing abdominal surgeries. Inactivation of DHT to 3α/β-diol for 24 h was measured in dexamethasone- or vehicle-treated cells. Specific downregulation of aldo-keto reductase 1C (AKR1C) enzymes in human preadipocytes was achieved using RNA interference. In whole adipose tissue sample, cortisol production was positively correlated with androgen inactivation in both subcutaneous and omental adipose tissue (P < 0.05). Maximal dexamethasone (1 μM) stimulation of DHT inactivation was higher in omental compared with subcutaneous fat from men as well as subcutaneous and omental fat from women (P < 0.05). A significant positive correlation was observed between BMI and maximal dexamethasone-induced DHT inactivation rates in subcutaneous and omental adipose tissue of men and women (r = 0.24, n = 26, P < 0.01). siRNA-induced downregulation of AKR1C2, but not AKR1C1 or AKR1C3, significantly reduced basal and glucocorticoid-induced androgen inactivation rates (P < 0.05). The inhibitory action of DHT on preadipocyte differentiation was potentiated following AKR1C2 but not AKR1C1 or AKR1C3 downregulation. Specifically, lipid accumulation, G3PDH activity, and FABP4 mRNA expression in differentiated preadipocytes exposed to DHT were reduced further upon AKR1C2 siRNA transfection. We conclude that glucocorticoid-induced androgen inactivation is mediated by AKR1C2 and is particularly effective in omental preadipocytes of obese men. The interplay between glucocorticoids and AKR1C2-dependent androgen inactivation may locally modulate adipogenesis and lipid accumulation in a depot-specific manner.
    AJP Endocrinology and Metabolism 01/2012; 302(8):E941-9. · 4.51 Impact Factor
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    ABSTRACT: The enzymatic pathways leading to the synthesis of bioactive steroids in the brain are now almost completely elucidated in various groups of vertebrates and, during the last decade, the neuronal mechanisms involved in the regulation of neurosteroid production have received increasing attention. This report reviews the current knowledge concerning the effects of neurotransmitters, peptide hormones, and neuropeptides on the biosynthesis of neurosteroids. Anatomical studies have been carried out to visualize the neurotransmitter- or neuropeptide-containing fibers contacting steroid-synthesizing neurons as well as the neurotransmitter, peptide hormones, or neuropeptide receptors expressed in these neurons. Biochemical experiments have been conducted to investigate the effects of neurotransmitters, peptide hormones, or neuropeptides on neurosteroid biosynthesis, and to characterize the type of receptors involved. Thus, it has been found that glutamate, acting through kainate and/or AMPA receptors, rapidly inactivates P450arom, and that melatonin produced by the pineal gland and eye inhibits the biosynthesis of 7α-hydroxypregnenolone (7α-OH-Δ(5)P), while prolactin produced by the adenohypophysis enhances the formation of 7α-OH-Δ(5)P. It has also been demonstrated that the biosynthesis of neurosteroids is inhibited by GABA, acting through GABA(A) receptors, and neuropeptide Y, acting through Y1 receptors. In contrast, it has been shown that the octadecaneuropetide ODN, acting through central-type benzodiazepine receptors, the triakontatetraneuropeptide TTN, acting though peripheral-type benzodiazepine receptors, and vasotocin, acting through V1a-like receptors, stimulate the production of neurosteroids. Since neurosteroids are implicated in the control of various neurophysiological and behavioral processes, these data suggest that some of the neurophysiological effects exerted by neurotransmitters and neuropeptides may be mediated via the regulation of neurosteroid production.
    Frontiers in Endocrinology 01/2012; 3:4.
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    ABSTRACT: Amphibians have been widely used to investigate the synthesis of biologically active steroids in the brain and the regulation of neurosteroid production by neurotransmitters and neuropeptides. The aim of the present review is to summarize the current knowledge regarding the neuroanatomical distribution and biochemical activity of steroidogenic enzymes in the brain of anurans and urodeles. The data accumulated over the past two decades demonstrate that discrete populations of neurons and/or glial cells in the frog and newt brains express the major steroidogenic enzymes and are able to synthesize de novo a number of neurosteroids from cholesterol/pregnenolone. Since neurosteroidogenesis has been conserved during evolution from amphibians to mammals, it appears that neurosteroids must play important physiological functions in the central nervous system of vertebrates.
    Frontiers in Endocrinology 01/2011; 2:79.
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    ABSTRACT: Intratumoral biosynthesis of hormone steroids is thought to play a role in the pathogenesis and development of human breast cancer. There is evidence that glucocorticoids may inhibit the development and progression of breast cancer. 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 is the enzyme which converts inactive cortisone to active cortisol. In order to study the expression of 11β-HSD type 1 in breast cancer and non-cancerous breast tissue, we have developed specific antibodies to 11β-HSD type 1 and proceeded to localization of the enzyme in 84 specimens of breast carcinoma and adjacent non-malignant tissues by immnohistochemistry. The results were correlated with the expression of androgen receptor, estrogen receptor, progesterone receptor, glucocorticoid receptor and CDC47, a cell division marker, as well as the tumor stage, tumor size, nodal status and menopausal status. The expression of 11β-HSD type 1 in 64% of breast cancer specimens appeared significantly lower than that observed in normal adjacent tissues (97% of cases being positive). There was no significant correlation between 11β-HSD type 1 expression and the clinicopathological parameters studied. The decrease in 11β-HSD type 1 expression in breast cancer as compared to that observed in the adjacent normal tissues may play a role in the development and/or progression of the cancer by modifying the intratumoral levels of glucocorticoids.
    Pathology & Oncology Research 01/2011; 17(3):627-32. · 1.56 Impact Factor
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    ABSTRACT: Adipose tissue glucocorticoid action relies on local enzymatic interconversion and glucocorticoid receptor (GR) availability. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), 2 (11β-HSD2) and hexose-6-phosphate dehydrogenase (H6PDH) are likely involved in glucocorticoid activation/inactivation within adipose tissue. We examined adipose tissue mRNA expression of genes related to glucocorticoid action and their association with total and visceral adiposity. Messenger RNA was measured in paired subcutaneous and omental fat samples obtained from 56 women (age: 47.3 ± 4.8 years, BMI: 27.1 ± 5.2 kg/m(2)) undergoing gynaecological surgery. Expression levels of 11β-HSD2, H6PDH and GRα were higher in omental adipose tissue while 11β-HSD1 expression was similar between fat compartments. Subcutaneous and omental 11β-HSD1 mRNA abundances were positively associated with total and visceral adiposity whereas omental H6PDH mRNA abundance was negatively associated with these measures. Only omental 11β-HSD1 mRNA expression remained significantly associated with visceral adipose tissue area following statistical adjustment for fat mass, age and menopausal status. Omental 11β-HSD1 mRNA expression explained 19.1% of the variance in visceral adipose tissue area. Omental fat tissue 11β-HSD-1 protein and cortisol levels were higher in visceral obese women, supporting findings obtained with 11β-HSD-1 mRNA. These results suggest that among the transcripts examined only omental 11β-HSD1 is independently associated with visceral obesity in women.
    The Journal of steroid biochemistry and molecular biology 03/2010; 122(1-3):28-34. · 2.66 Impact Factor
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    ABSTRACT: 5a-Reductases are crucial enzymes involved in the biosyn-thesis of dihydrotestosterone, the most potent natural andro-gen. To date, three types of 5a-reductases, chronologically named types 1, 2 and 3 5a-reductases (SRD5a-1, 2 and 3) have been described. In the present paper, we characterized the activity and compared the mRNA expression levels of SRD5a-3 with those of SRD5a-1 and 2 in various human tissues, and determined its sensitivity to finasteride and dutasteride. We have established HEK-293 cell line that sta-bly expressed SRD5a-3 for studying its activity and the inhibitory effect of finasteride, using w 14 Cxlabeled steroids. mRNA expression levels were quantified using real-time PCR in many male and female human tissues including the prostate, adipose tissue, mammary gland, as well as breast and prostate cancer cell lines. Incubation of HEK-SRD5a-3 cells with w 14 Cx4-androstenedione and w 14 Cxtestosterone allowed us to show that SRD5a-3 can catalyze very effi-ciently both substrates 4-androstenedione and testosterone into 5a-androstanedione and dihydrotestosterone, respective-ly. We observed that the affinity of the enzyme for 4-andros-tenedione is higher than for testosterone. The activity of SRD5a-3 and SRD5a-2 are similarly sensitive to finasteride, whereas dutasteride is a much more potent inhibitor of SRD5a-3 than SRD5a-2. Tissue distribution analysis shows that SRD5a-3 mRNA expression levels are higher than those of SRD5a-1 and SRD5a-2 in 20 analyzed tissues. In partic-ular, it is highly expressed in the skin, brain, mammary gland and breast cancer cell lines, thus suggesting that SRD5a-3 could play an important role in the production of androgens in these and other peripheral tissues.
    Hormone Molecular Biology and Clinical Investigation. 01/2010; 2(3).
  • Samson M, F. Labrie, V. Luu-The
    Hormone molecular biology and clinical investigation 01/2010; 1:67-72.
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    Van Luu-The, Fernand Labrie
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    ABSTRACT: There is an increasing number of differences reported between the steroidogenesis pathways described in the traditional literature related to gonadal steroidogenesis and the more recent observations achieved using new technologies, especially molecular cloning, pangenomic expression studies, precise quantification of mRNA expression using real-time PCR, use of steroidogenic enzymes stably transfected in cells, detailed enzymatic activity analysis in cultured cell lines and mass spectrometry analysis of steroids. The objective of this chapter is to present steroidogenesis in the light of new findings that demonstrate pathways of biosynthesis of estradiol (E(2)) and dihydrotestosterone (DHT) from adrenal dehydroepiandrosterone (DHEA) in peripheral intracrine tissues which do not involve testosterone as intermediate as classically found in the testis and ovary. Steroidogenic enzymes different from those of the ovary and testis act in a tissue-specific manner to catalyze the transformation of DHEA into active sex steroids. These new pathways are especially important in post-menopausal women where all estrogens and practically all androgens are made at their site of action in peripheral tissues from DHEA, the precursor of adrenal origin. In men, on the other hand, from 40 to 50% of androgens are made in peripheral tissues from adrenal DHEA, thus indicating the major importance of the intracrine pathways in both men and women. We also examine the molecular evolution of steroidogenic enzymes which explains the major differences in steroid metabolism observed between laboratory animals and humans.
    Progress in brain research 01/2010; 181:177-92. · 4.19 Impact Factor
  • Hormone molecular biology and clinical investigation 01/2010; 2(3):311-318.
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    ABSTRACT: 17β-HSD, 17β-hydroxysteroid dehydrogenase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 4-dione, 4-androstenedione; 5α-dione, 5α-androstane-3,17 dione; 5α-Red, 5α-reductase; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; T, testosterone
    Journal of Investigative Dermatology 10/2009; 130(2):602-4. · 6.19 Impact Factor
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    ABSTRACT: 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
    Journal of Medicinal Chemistry 09/2009; 52(23):7488-502. · 5.61 Impact Factor
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    ABSTRACT: The occurrence of several enzymes responsible for the biosynthesis of neurosteroids in the brain of adult frogs is now firmly established but the expression of these enzymes during ontogenesis has not yet been investigated. In the present report, we describe the immunohistochemical distribution and biological activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 5alpha-reductase (5alpha-R) in the brain of the European green frog, Rana esculenta, during larval development. The spatio-temporal distribution of 3beta-HSD and 5alpha-R immunoreactivities in the tadpole brain was generally different, although these two enzymes were occasionally detected in the same areas such as the olfactory bulbs and cerebellum. Identification of neurons based on their morphological aspect as well as labeling of astrocytes with an antiserum against glial fibrillary acidic protein (GFAP) revealed that, in the tadpole brain, 3beta-HSD- and 5alpha-R-immunoreactive materials were contained in both neurons and glial cells. Incubation of tadpole brain explants with [(3)H]-pregnenolone resulted in the formation of several tritiated steroids including progesterone, 17-hydroxyprogesterone, androstenedione, 5alpha-dihydroprogesterone and 5alpha-dihydrotestosterone. The present study provides the first immunocytochemical mapping of two key steroidogenic enzymes in the developing frog brain. The data also indicate that neurosteroid biosynthesis occurs in the brain of tadpoles, as previously shown for adult amphibians, birds and mammals. The transient expression of steroidogenic enzymes in several regions of the tadpole brain suggests that, in amphibians, neurosteroids may be implicated in neurotrophic activities during larval development.
    Journal of chemical neuroanatomy 09/2009; 39(1):35-50. · 1.75 Impact Factor
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    ABSTRACT: To examine the effects of aromatizable or nonaromatizable androgens on abdominal subcutaneous (SC) and omental (OM) adipose tissue lipid metabolism and adipogenesis in men and women. Primary organ and preadipocyte cultures were established from surgical samples obtained in men (n = 22) and women undergoing biliopancreatic diversions (n = 12) or gynaecological surgeries (n = 8). Cultures were treated with testosterone, dihydrotestosterone (DHT) and methyltrienolone (R1881). Heparin-releasable lipoprotein lipase (HR-LPL) activity, glycerol release, adiponectin secretion, glycerol-3-phosphate dehydrogenase activity and lipid accumulation were measured. In organ cultures from men, DHT had a statistically significant inhibitory effect on HR-LPL activity in the OM compartment. Testosterone significantly inhibited HR-LPL activity in SC and OM cultures. In women, high DHT concentrations tended to inhibit HR-LPL activity in OM cultures. Minor androgenic effects were observed for basal and isoproterenol-stimulated lipolysis as well as adiponectin release in men. On the other hand, adipocyte differentiation was significantly and dose-dependently inhibited by DHT, testosterone and R1881 in SC and OM cultures from both sexes. These effects did not differ according to adipose tissue depot but appeared to be more pronounced in women than in men. Androgens slightly decreased HR-LPL activity in adipose tissue organ cultures, but markedly inhibited adipogenesis in SC and OM primary preadipocyte cultures in both sexes. Androgenic effects on adipose tissue in men vs. women may not differ in terms of direction but in the magnitude of their negative impact on adipogenesis and lipid synthesis.
    Clinical Endocrinology 07/2009; 72(2):176-88. · 3.40 Impact Factor
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    ABSTRACT: Episkin and full thickness model from Episkin (FTM) are human skin models obtained from in vitro growth of keratinocytes into the five typical layers of the epidermis. FTM is a full thickness reconstructed skin model that also contains fibroblasts seeded in a collagen matrix. To assess whether enzymes involved in chemical detoxification are expressed in Episkin and FTM and how their levels compare with the human epidermis, dermis and total skin. Quantification of the mRNA expression levels of phases 1 and 2 metabolizing enzymes in cultured Episkin and FTM and human epidermis, dermis and total skin using Realtime PCR. The data show that the expression profiles of 61 phases 1 and 2 metabolizing enzymes in Episkin, FTM and epidermis are generally similar, with some exceptions. Cytochrome P450-dependent enzymes and flavin monooxygenases are expressed at low levels, while phase 2 metabolizing enzymes are expressed at much higher levels, especially, glutathione-S-transferase P1 (GSTP1) catechol-O-methyl transferase (COMT), steroid sulfotransferase (SULT2B1b), and N-acetyl transferase (NAT5). The present study also identifies the presence of many enzymes involved in cholesterol, arachidonic acid, leukotriene, prostaglandin, eicosatrienoic acids, and vitamin D3 metabolisms. The present data strongly suggest that Episkin and FTM represent reliable and valuable in vitro human skin models for studying the function of phases 1 and 2 metabolizing enzymes in xenobiotic metabolisms. They could be used to replace invasive methods or laboratory animals for skin experiments.
    The Journal of steroid biochemistry and molecular biology 06/2009; 116(3-5):178-86. · 2.66 Impact Factor
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    ABSTRACT: Modulation of adipose tissue exposure to active glucocorticoids by type 1 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1) is involved in abdominal obesity of rodent models, but only a few studies have related 11 beta-HSD1 oxoreductase activity to fat distribution in humans. The objective of the study was to examine the link between 11 beta-HSD1 oxoreductase activity, fat distribution patterns, and the metabolic profile in women. Omental (OM) and sc adipose tissue samples were obtained from 36 lean to obese women (aged 47.2 +/- 5.3 yr; body mass index 29.1 +/- 5.2 kg/m(2)) undergoing gynecological surgery. Measures of body composition, fat distribution, blood lipids, and insulin sensitivity were obtained. 11 beta-HSD1 oxoreductase activity was measured over a 24-h period by the reduction of [(14)C]cortisone in adipose tissue homogenates. 11 beta-HSD1 oxoreductase activity was higher in OM compared with sc adipose tissue (9.6 +/- 4.9 vs. 7.9 +/- 4.2 pmol/mg x h, P < 0.01). OM 11 beta-HSD1 oxoreductase activity was positively associated with OM adipocyte size (r = 0.67, P < 0.0001) and visceral adipose tissue area (r = 0.57, P < 0.0003). A positive correlation was also observed between the OM/sc 11 beta-HSD1 oxoreductase activity ratio and the OM/sc adipocyte size ratio (r = 0.37, P < 0.05) as well as the visceral/sc adipose tissue area ratio (r = 0.36, P < 0.05). Women in the highest tertile of OM 11 beta-HSD1 oxoreductase activity had larger OM adipocytes, increased OM lipolysis, increased lipoprotein lipase activity, decreased high-density lipoprotein cholesterol, decreased adiponectin levels, and an increased homeostasis model assessment of insulin resistance index compared with women in the lower tertile (P < 0.05). These results suggest that a relatively higher 11 beta-HSD1 activity in OM vs. sc adipose tissue is associated with preferential visceral fat accumulation and concomitant metabolic alterations.
    The Journal of clinical endocrinology and metabolism 06/2009; 94(9):3550-7. · 6.50 Impact Factor
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    ABSTRACT: Estradiol (E2) plays a crucial role in all reproduction processes. In the placenta, it is well recognized that E2 is synthesized from fetal dehydroepiandrosterone sulfate (DHEAS). However, there is some controversy about the biosynthetic pathway involved, some authors suggest that E2 is produced by aromatization of testosterone (T), while others suggest that E2 is produced by the conversion of estrone (E1) into E2 by type 1 17beta-HSD, subsequent to the aromatization of 4-androstenedione (4-dione) into E1. In the present report, using the precursor [(14)C]DHEA, inhibitors of steroidogenic enzymes (chemical inhibitors and siRNA) and a choriocarcinoma (JEG-3) cell line that expresses all the enzymes necessary to transform DHEA into E2, we could determine the sequential steps and the specific steroidogenic enzymes involved in the transformation of DHEA into E2. Quantification of mRNA expression levels using real-time PCR, strongly suggests that type 1 3beta-hydroxysteroid dehydrogenase (3beta-HSD1), aromatase and type 1 17beta-HSD (17beta-HSD1) that are highly expressed in JEG-3 cells are the enzymes responsible for the transformation of DHEA into E2. Analysis of the intermediates produced in the absence and presence of 3beta-HSD, aromatase and 17beta-HSD1 inhibitors permits to determine the following sequential steps: DHEA is transformed into 4-dione by 3beta-HSD1, then 4-dione is aromatized into E1 by aromatase and E1 is finally transformed into E2 by 17beta-HSD1. Our data are clearly in favor of the pathway in which the step of aromatization precedes the step of reduction by 17beta-HSD.
    The Journal of steroid biochemistry and molecular biology 06/2009; 116(3-5):154-9. · 2.66 Impact Factor

Publication Stats

6k Citations
936.99 Total Impact Points

Institutions

  • 1989–2013
    • Laval University
      • • Department of Molecular Medicine
      • • Department of Medicine
      Québec, Quebec, Canada
  • 2005–2009
    • Università degli Studi di Genova
      Genova, Liguria, Italy
  • 2001–2009
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1999–2007
    • Université de Rouen
      • Microbiology Signals and Microenvironment Lab (LMSM) (EA 4312)
      Mont-Saint-Aignan, Upper Normandy, France
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1996–2005
    • Centre hospitalier de l'Université de Montréal (CHUM)
      Montréal, Quebec, Canada
  • 1992–2005
    • Université du Québec
      Québec, Quebec, Canada
    • The University of Western Ontario
      London, Ontario, Canada
  • 2001–2003
    • Centre Hospitalier Universitaire de Québec (CHUQ)
      Québec, Quebec, Canada
  • 1994
    • Endocrinology Research Centre
      Moskva, Moscow, Russia
  • 1992–1993
    • Lawson Health Research Institute
      London, Ontario, Canada