DHEA and the Intracrine Formation of Androgens and Estrogens in Peripheral Target Tissues: Its Role during Aging

Labrie, Fernand; Bélanger, Alain; Luu‐The, Van; Labrie, Claude; Simard, Jacques; Cusan, Lionel; Gomez, José‐Luis; Candas, Bernard

doi:10.1016/s0039-128x(98)00007-5

Cited by 303 publications

(196 citation statements)

References 27 publications

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“…DHEA is widely used as an overthe-counter dietary supplement with unsubstantiated claims of beneficial effects on body composition, cardiometabolic, immune, and neurobiological functions [16] as well as uncertain long-term safety. Humans and other primates are unique among animal species in that their adrenal glands secrete large amounts of DHEA and DHEA-S [5,12]. DHEA has been shown to exert many of its effects via the AR and/or estrogen receptor (ER) following its enzymatic conversion to androgen or estrogen [17], although direct effects of DHEA on the AR and ER have also been demonstrated [18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…It is increasingly consumed as an over-the-counter dietary supplement for its purported antiaging effects, yet its usefulness, long-term safety and effects on prostate tissues remain uncertain [2]. Prostate stromal and epithelial cells possess the enzymatic machinery to metabolize DHEA to more active androgenic and/or estrogenic steroids [3][4][5] (intracrine) and express secondary mediators (paracrine) for epithelial growth and differentiation. Defining DHEA and other steroid hormonal responses in the prostate requires simulation of the intracrine and paracrine effects of hormones provided by stromal cells.…”

Section: Introductionmentioning

confidence: 99%

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Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells

Arnold

Gray

Jacobowitz

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Dehydroepiandrosterone (DHEA) is commonly used as a dietary supplement and may affect prostate pathophysiology when metabolized to androgens and/or estrogens. Human prostate LAPC-4 cancer cells with a wild type androgen receptor (AR), were treated with DHEA, androgens (DHT, T, or R1881), and E 2 and assayed for PSA protein and gene expression. In LAPC-4 monocultures, DHEA and E 2 induced little or no increase in PSA protein or mRNA expression compared to androgentreated cells. When prostate cancer-associated (6S) stromal cells were added in coculture, DHEA stimulated LAPC-4 cell PSA protein secretion to levels approaching induction by DHT. Also, DHEA induced 15-fold more PSA mRNA in LAPC-4 cocultures than in monocultures. LAPC-4 proliferation was increased 2-3 fold when cocultured with 6S stromal cells regardless of hormone treatment. DHEA-treated 6S stromal cells exhibited a dose-and time-dependent increase in T secretion, demonstrating stromal cell metabolism of DHEA to T. Coculture with non-cancerous stroma did not induce LAPC-4 PSA production, suggesting a differential modulation of DHEA effect in a cancerassociated prostate stromal environment. This coculture model provides a research approach to reveal detailed endocrine, intracrine, and paracrine signaling between stromal and epithelial cells that regulate tissue homeostasis within the prostate, and the role of the tumor microenvironment in cancer progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells

Arnold

Gray

Jacobowitz

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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“…Another SOAT substrate, DHEAS, is synthesised and secreted by the adrenal cortex and can be reversibly hydrolysed to the corresponding free steroid DHEA. DHEAS serves as the principal conjugated pro-hormone for the biosynthesis of oestrogenic and androgenic steroids in peripheral tissues (Baulieu 1996;Labrie et al 1998). Plasma concentrations of DHEAS are in the range of 2-10 μM in young adults (Baulieu 1996), which is near the K m for in vitro DHEAS transport by Soat (K m =30 μM).…”

Section: Pharmacological Inhibition Of the Asbtmentioning

confidence: 99%

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Geyer

Wilke

Petzinger

2006

Naunyn Schmied Arch Pharmacol

158

144

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The solute carrier family 10 (SLC10) comprises two sodium-dependent bile acid transporters, i.e. the Na + / taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). These carriers are essentially involved in the maintenance of the enterohepatic circulation of bile acids mediating the first step of active bile acid transport through the membrane barriers in the liver (NTCP) and intestine (ASBT). Recently, four new members of the SLC10 family were described and referred to as P3 (SLC10A3), P4 (SLC10A4), P5 (SLC10A5) and sodium-dependent organic anion transporter (SOAT; SLC10A6). Experimental data supporting carrier function of P3, P4, and P5 is currently not available. However, as demonstrated for SOAT, not all members of the SLC10 family are bile acid transporters. SOAT specifically transports steroid sulfates such as oestrone-3-sulfate and dehydroepiandrosterone sulfate in a sodium-dependent manner, and is considered to play an important role for the cellular delivery of these prohormones in testes, placenta, adrenal gland and probably other peripheral tissues. ASBT and SOAT are the most homologous members of the SLC10 family, with high sequence similarity (∼70%) and almost identical gene structures. Phylogenetic analyses of the SLC10 family revealed that ASBT and SOAT genes emerged from a common ancestor gene. Structure-activity relationships of NTCP, ASBT and SOAT are discussed at the amino acid sequence level.Based on the high structural homology between ASBT and SOAT, pharmacological inhibitors of the ASBT, which are currently being tested in clinical trials for cholesterollowering therapy, should be evaluated for their crossreactivity with SOAT.

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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%

“…To date, no such DHEA(S) receptor has been found and it was consequently concluded that these compounds do not act like other steroid hormones, which directly regulate gene expression (Mohan and Cleary 1992). In fact, it has been suggested that the intracrine metabolism of DHEA(S) is an important factor in mediating their effects (Labrie et al 1998). Non-genomic effects of DHEA(S) are obviously also responsible for their actions in the CNS (Wolf and Kirschbaum 1999).…”

mentioning

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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DHEA and the Intracrine Formation of Androgens and Estrogens in Peripheral Target Tissues: Its Role during Aging

Cited by 303 publications

References 27 publications

Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells

Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

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

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