Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease

Labrie, Fernand; Luu‐The, Van; Lin, Sheng‐Xiang; Simard, Jacques; Labrie, Claude; El‐Alfy, Mohamed; Pelletier, Georges; Bélanger, Alain

doi:10.1677/jme.0.0250001

Cited by 259 publications

(175 citation statements)

References 90 publications

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“…Similar functions are found for other steroid dehydrogenases, which act at C3 and C17 to regulate the local concentrations of androgens and [8,14,15,17] estrogens.…”

Section: Regulation Of the Steroid Response By Selective Expression Osupporting

confidence: 56%

“…Flexibility and complexity in vertebrate differentiation and development also arises from temporal and tissue-specific expression of enzymes that metabolize steroids [12][13][14][15][16][17].…”

Section: Regulation Of the Steroid Response By Selective Expression Omentioning

confidence: 99%

“…I propose that the emergence in vertebrates of this ligand-based mechanism for regulating gene transcription, combined with regulation of steroid hormone access to their receptors by enzymes (Fig. 2) [12][13][14][15][16][17], was an important element in complex differentiation and development found in humans and other vertebrates. In mammals, 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-type 1) and 11βHSD-type 2, which have less than 20% sequence identity, preferentially catalyze the reduction and oxidation of a ketone and alcohol, respectively, at C11 on glucocorticoids.…”

Section: Introductionmentioning

confidence: 99%

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Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

Baker

2003

BioEssays

105

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SummaryVarious explanations have been proposed to account for complex differentiation and development in humans, despite the human genome containing only two to three times the number of genes in invertebrates. Ignored are the actions of adrenal and sex steroids-androgens, estrogens, glucocorticoids, mineralocorticoids, and progestins-which act through receptors that arose from an ancestral nuclear receptor in a protochordate. This ligand-based mechanism is unique to vertebrates and was integrated into the already robust network of transcription factors in invertebrates. Adrenal and sex steroids influence almost all aspects of vertebrate differentiation and development. I propose that evolution of this ligand-based mechanism in a primitive vertebrate was an important contribution to vertebrate complexity. Sequencing of genomes from a cephalochordate, such as amphioxus, and from hagfish and lamprey will establish early events in the evolution of steroid hormone signaling, and also allow genetic studies to elucidate how vertebrate complexity depends on steroid hormones.

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“…Similar functions are found for other steroid dehydrogenases, which act at C3 and C17 to regulate the local concentrations of androgens and [8,14,15,17] estrogens.…”

Section: Regulation Of the Steroid Response By Selective Expression Osupporting

confidence: 56%

Section: Regulation Of the Steroid Response By Selective Expression Omentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

Baker

2003

BioEssays

105

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“…To date, at least 8 isoforms of the 17HSD enzyme with different substrate and cofactor specificities, tissue distributions and subcellular localizations have been characterized. 8,9 Of these isoforms, 17HSD type 1 and type 2 catalyze opposite reactions of estrogen metabolism. 17HSD type 1 is the predominant enzyme involved in estradiol biosynthesis (E1 to E2), and it is expressed in cells of placental and ovarian origin 10,11 as well as in breast tissue.…”

mentioning

confidence: 99%

Downregulation of estrogen‐metabolizing 17β‐hydroxysteroid dehydrogenase Type 2 expression correlates inversely with Ki67 proliferation marker in colon‐cancer development

Oduwole

Isomaa

Nokelainen

et al. 2001

Intl Journal of Cancer

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The 17HSDs are a group of isozymes that catalyze the interconversion between high-activity 17␤-hydroxysteroids and low-activity 17-ketosteroids. In the present study, we characterized the expression of 17HSD types 1 and 2 in normal and malignant gastrointestinal tissues and cells. Using the colon as a model for cancer of the gastrointestinal tract, expression of the 17HSD enzymes in cancer development was studied and correlated with proliferation and differentiation markers as assessed by Ki67 and mucin staining, respectively. In normal colon and small intestine, 17HSD type 2 mRNA was expressed in the surface epithelial cells and, to a lesser extent, in the cryptal epithelial cells. In colon-cancer specimens, 17HSD type 2 expression was downregulated both in the tissues and in the cell lines and correlated inversely with the proliferation marker. No expression for the 17HSD type 1 enzyme was observed in normal or cancerous gastrointestinal tract tissues. In line with the expression studies, 17HSD activity measurements with colon cells showed that only the oxidative conversion of E2 to E1 was present, and Northern blot analysis showed the signal only for 17HSD type 2. Localization of the ERs ␣ and ␤, assessed by immunohistochemistry and in situ hybridization, showed the presence of ER␤ in the lamina propria of the colon. Our study shows that 17HSD type 2 expression is associated with the functional integrity of the gastrointestinal tract. The decrease in expression of the type 2 enzyme may increase estrogen influence in colon cancer. © 2002 Wiley-Liss, Inc. Key words: colon carcinoma; estrogen; hydroxysteroid dehydrogenase; cell proliferation; cell differentiationEpidemiologic studies 1,2 and in vitro studies with colon-cancer cell lines 3 suggest the involvement of estrogens in the development and progression of gastrointestinal cancer. [3][4][5] Contrary to this, however, is the indication that HRT is effective at reducing the incidence of colon cancer. 6 The mechanism underlying the sex steroid-mediated effects in normal gastrointestinal physiology and its involvement in neoplastic development and progression, if any, are far from clear.The 17HSDs play pivotal roles in the regulation of the physiologic activities of sex steroid hormones by catalyzing the oxidation or reduction of 17␤-hydroxy-and 17-ketosteroids, respectively. 7,8 17HSDs regulate the concentrations of the active sex steroids that bind to the respective steroid receptors to regulate gene expression in target cells. To date, at least 8 isoforms of the 17HSD enzyme with different substrate and cofactor specificities, tissue distributions and subcellular localizations have been characterized. 8,9 Of these isoforms, 17HSD type 1 and type 2 catalyze opposite reactions of estrogen metabolism. 17HSD type 1 is the predominant enzyme involved in estradiol biosynthesis (E1 to E2), and it is expressed in cells of placental and ovarian origin 10,11 as well as in breast tissue. 12 On the other hand, 17HSD type 2 catalyzes the oxidation of estrogens (E2 to E1...

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“…The intracrine metabolism of DHEA is suggested to play a major role in mediating its peripheral effects (Labrie et al 1998(Labrie et al , 2000. In the rodent brain, the formation of DHEA metabolites with reduced pyridine nucleotides as coenzymes is primarily catalysed via 7a-hydroxylase and 17b-HSD activity (Baulieu and Robel 1996).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7α‐hydroxylase and 17‐ketosteroid reductase activity in the human brain

Steckelbroeck¹,

Watzka²,

Lütjohann³

et al. 2002

Journal of Neurochemistry

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Dehydroepiandrosterone and its sulphate are important factors for vitality, development and functions of the CNS. They were found to be subjects to a series of enzyme-mediated conversions within the rodent CNS. In the present study, we were able to demonstrate for the first time that membraneassociated dehydroepiandrosterone 7a-hydroxylase activity occurs within the human brain. The cytochrome P450 enzyme demonstrated a sharp pH optimum between 7.5 and 8.0 and a mean K M value of 5.4 lM, corresponding with the presence of the oxysterol 7a-hydroxylase CYP7B1. Real-time RT-PCR analysis verified high levels of CYP7B1 mRNA expression in the human CNS. The additionally observed conversion of dehydroepiandrosterone via cytosolic 17b-hydroxysteroid dehydrogenase activity could be ascribed to the activity of an enzyme with a broad pH optimum and an undetectably high K M value. Subsequent experiments with cerebral neocortex and subcortical white matter specimens revealed that 7a-hydroxylase activity is significantly higher in the cerebral neocortex than in the subcortical white matter (p < 0.0005), whereas in the subcortical white matter, 17b-hydroxysteroid dehydrogenase activity is significantly higher than in the cerebral neocortex (p < 0.0005). No sex differences were observed. In conclusion, the high levels of CYP7B1 mRNA in brain tissue as well as in a variety of other tissues in combination with the ubiquitous presence of 7a-hydroxylase activity in the human temporal lobe led us to assume a neuroprotective function of the enzyme such as regulation of the immune response or counteracting the deleterious effects of neurotoxic glucocorticoids, rather than a distinct brain specific function such as neurostimulation or neuromodulation.

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Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease

Cited by 259 publications

References 90 publications

Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

Downregulation of estrogen‐metabolizing 17β‐hydroxysteroid dehydrogenase Type 2 expression correlates inversely with Ki67 proliferation marker in colon‐cancer development

Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7α‐hydroxylase and 17‐ketosteroid reductase activity in the human brain

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