Pregnenolone and dehydroepiandrosterone as precursors of native 7-hydroxylated metabolites which increase the immune response in mice

Morfin, Robert; Courchay, Guy

doi:10.1016/0960-0760(94)90176-7

Cited by 133 publications

(71 citation statements)

References 23 publications

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“…Data from both in vitro and in vivo studies suggest that 7␣-OH-DHEA has immunostimulating activity (4,(8)(9)(10)(11). In this regard, it is of interest that 7␣-OH-DHEA appeared to be more active than DHEA in stimulating the production of antilysozyme antibodies (8) and enhancing the immune response to tetanus toxoid and Bordetella pertussis antigens (10,12). Moreover, it has been demonstrated that 7␣-OH-DHEA prevents the immunosuppressive effects of glucocorticoids in vitro (4,8).…”

mentioning

confidence: 99%

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

Dulos¹,

Vleuten²,

Kavelaars³

et al. 2005

Arthritis & Rheumatism

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Objective. The cytochrome P450 enzyme CYP7B catalyzes the conversion of dehydroepiandrosterone (DHEA) into 7␣-hydroxy-DHEA (7␣-OH-DHEA). This metabolite can stimulate the immune response. We previously reported that the severity of murine collageninduced arthritis is correlated with CYP7B messenger RNA (mRNA) expression and activity in the arthritic joint. The purpose of this study was to investigate the presence of 7␣-OH-DHEA in synovial samples and the cytokine regulation of CYP7B activity in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).Methods. The presence of 7␣-OH-DHEA was examined in synovial biopsy tissues, synovial fluid, and serum by radioimmunoassay. The effect of cytokines on CYP7B mRNA expression and CYP7B activity in FLS was examined by determining the formation of the CYP7B enzyme product 7␣-OH-DHEA with the use of high-performance liquid chromatography.Results. The CYP7B enzyme product 7␣-OH-DHEA was found in synovial biopsy tissues, synovial fluid, and serum from RA patients. The proinflammatory cytokines tumor necrosis factor ␣ (TNF␣), interleukin-1␣ (IL-1␣), IL-1␤, and IL-17 up-regulated CYP7B activity in an FLS cell line 2-10-fold. Enhanced CYP7B activity was correlated with an increase in CYP7B mRNA. The cytokine transforming growth factor ␤ inhibited CYP7B activity. Moreover, CYP7B activity was detected in 10 of 13 unstimulated synovial fibroblast cell lines. Stimulation with TNF␣ increased CYP7B activity in all cell lines tested.Conclusion. Exposure to the proinflammatory cytokines TNF␣, IL-1␣, IL-1␤, and IL-17 increases CYP7B activity in synovial tissue. Increased CYP7B activity leads to higher levels of the DHEA metabolite 7␣-OH-DHEA in synovial fluid, which may contribute to the maintenance of the chronic inflammation observed in RA patients.

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confidence: 99%

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

Dulos¹,

Vleuten²,

Kavelaars³

et al. 2005

Arthritis & Rheumatism

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“…One key study would be to treat Cyp7b knock-out mice (Rose et al, 2001) with PREG or DHEA; the memory-enhancing effects reported previously in mice (Flood et al, , 1995 should be absent in the Cyp7b knock-out mice if these steroids require activation by 7␣-hydroxylation. Consistent with the 7␣-hydroxy steroids being active, peripheral injection of both 7␣-hydroxyPREG and 7␣-hydroxyDHEA have been reported to increase immune responses in mice (Morfin and Courchay, 1994). In addition, 7␣-hydroxyDHEA can be further converted to 7-oxo-DHEA by 11␤-HSD1 (Robinzon et al, 2003), itself widespread in the CNS (Moisan et al, 1990), and 7-oxo-DHEA reverses scopolamine-induced memory impairments in young mice (Shi et al, 2000).…”

Section: Discussionmentioning

confidence: 70%

“…Although recent studies have reported anti-glucocorticoid, immunomodulatory, and antiapoptotic effects of 7␣-hydroxylated DHEA (Loria and Padgett, 1998;Hampl et al, 2000;Morfin and Starka, 2001;Pringle et al, 2003) and 7␣-hyroxyPREG (Morfin and Courchay, 1994), the effect of the CYP7B metabolites on memory have not been examined. Although CYP7B bioactivity was assayed with [ 14 C]DHEA as the preferred substrate based on previous findings (Akwa et al, 1992;Rose et al, 1997), we chose to examine the effects of PREG and its 7␣-hydroxylated metabolite on memory in the aged-impaired rats because this is the more abundant neurosteroid in rodent brain.…”

Section: Discussionmentioning

confidence: 99%

Central Administration of a Cytochrome P450-7B Product 7α-Hydroxypregnenolone Improves Spatial Memory Retention in Cognitively Impaired Aged Rats

Yau¹,

Noble²,

Graham³

2006

J. Neurosci.

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Pregnenolone (PREG) and dehydroepiandrosterone (DHEA) have been reported to improve memory in aged rodents. In brain, these neurosteroids are transformed predominantly into 7␣-hydroxylated metabolites by the cytochrome P450-7B1 (CYP7B). The biological role of steroid B-ring hydroxylation is unclear. It has been proposed to generate bioactive derivatives that enhance cognition, immune, and other physiological processes. In support, 7␣-hydroxylated DHEA increases the immune response in mice with greater potency than the parent steroid. Whether the memory-enhancing effects of PREG in rats is mediated via its 7␣-hydroxylated metabolite 7␣-hydroxyPREG is not known. We investigated this by treating memory-impaired aged rats (identified by their spatial memory performances in the Morris water maze task compared with young controls) with 7␣-hydroxyPREG or PREG administered intracerebroventricularly using osmotic minipumps and then tested the rats during week 2 of steroid treatment in the eight-arm radial-arm version of the water maze (RAWM) that allows repeated assessment of learning. CYP7B bioactivity in hippocampal tissue (percentage conversion of [ 14 C]DHEA to [ 14 C]7␣-hydroxyDHEA) was decreased selectively in memory-impaired aged rats compared with both young and memory-intact aged rats. 7␣-hydroxyPREG (100 ng/h) but not PREG (100 ng/h) administration to memory-impaired aged rats for 11 d enhanced spatial memory retention (after a 30 min delay between an exposure trial 1 and test trial 2) in the RAWM. These data provide evidence for a biologically active enzyme product 7␣-hydroxyPREG and suggests that reduced CYP7B function in the hippocampus of memory-impaired aged rats may, in part, be overcome by administration of 7␣-hydroxyPREG.

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“…Consequently, one might presume an essential metabolic role of DHEA 7a-hydroxylase activity in the CNS. DHEA as well as D5-androstenediol and, in particular, their 7-hydroxylated metabolites possess immunomodulatory and antiglucocorticoid properties (Morfin and Courchay 1994;Padgett and Loria 1994;Hampl et al 1997;Loria 1997;Lafaye et al 1999). Therefore, it might be assumed that endocrine regulation of the immune response or counteracting the deleterious effects of neurotoxic glucocorticoids is a possible function of cerebral 7a-hydroxylase and 17-ketosteroid reductase activity.…”

Section: Discussionmentioning

confidence: 99%

“…The biological significance of the 7a-hydroxylation and the 17-ketosteroid reduction of DHEA in brain tissue remains to be elucidated. So far, it could be demonstrated that DHEA as well as D5-androstenediol and, in particular, their 7-hydroxylated metabolites possess immunomodulatory and antiglucocorticoid properties (Morfin and Courchay 1994;Padgett and Loria 1994;Hampl et al 1997;Loria 1997;Lafaye et al 1999). Increased DHEA and 7a-hydroxy-DHEA serum levels were found in patients with Alzheimer's disease (Attal-Khemis et al 1998).…”

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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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Pregnenolone and dehydroepiandrosterone as precursors of native 7-hydroxylated metabolites which increase the immune response in mice

Cited by 133 publications

References 23 publications

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

Central Administration of a Cytochrome P450-7B Product 7α-Hydroxypregnenolone Improves Spatial Memory Retention in Cognitively Impaired Aged Rats

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

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