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

Steckelbroeck, Stephan; Watzka, Matthias; Lütjohann, Dieter; Makiola, Paul; Nassen, Alexander; Hans, Volkmar; Clusmann, Hans; Reissinger, Annette; Ludwig, Michael; Siekmann, Lothar; Klingmüller, Dietrich

doi:10.1046/j.1471-4159.2002.01187.x

Cited by 59 publications

(38 citation statements)

References 63 publications

(69 reference statements)

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“…This cytochrome P450, which is a 7a-hydroxylase highly specific for 24S-hydroxycholesterol, was originally cloned as liver specific species [21]. Subsequent investigations have identified Cyp39a1 mRNA or protein in brain or the non-pigmented epithelium of the retina [23,24]. To the best of our knowledge, this is the first demonstration of pharmacological regulation of CYP39A1.…”

Section: Cyp7b1mentioning

confidence: 81%

Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors

Shafaati

O’Driscoll

Björkhem

et al. 2009

Biochemical and Biophysical Research Communications

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Keywords:24S-hydroxycholesterol CYP46A1 CYP39A1 Epigentics Histone deacetylase inhibitor Oxysterol Brain cholesterol a b s t r a c tThe mechanistic basis for the tissue specific expression of cholesterol elimination pathways is poorly understood. To gain additional insight into this phenomenon we considered it of interest to investigate if epigenetic mechanisms are involved in the regulation of the brain-specific enzyme cholesterol 24-hydroxylase (CYP46A1), a key regulator of brain cholesterol elimination. We demonstrated a marked time-dependent derepression of the expression of CYP46A1, in response to treatment with the potent histone deacetylase (HDAC) inhibitor Trichostatin A. The pattern of expression of the genes in the genomic region surrounding CYP46A1 was found to be diametrically opposite in brain and liver. Intraperitoneal injection of HDAC inhibitors in mice led to a significant derepression of hepatic Cyp46a1 mRNA expression and tissue specific changes in Hmgcr and Cyp39a1 mRNA expression. These results are discussed in the context of the phenomenology of tissue specific cholesterol balance.Ó 2008 Elsevier Inc. All rights reserved.Although all nucleated cells are capable of cholesterol synthesis, their ability to do so varies over several orders of magnitude. In the adult state most organisms have established a certain level of tissue specialisation [1]. The rate of cholesterol synthesis and the cholesterol content of a given tissue are not necessarily directly related, e.g. the adult brain contains more than 25% of whole body cholesterol but turns over only 0.03% of its cholesterol content each day. This turnover is much lower than the developing brain [1] where cholesterol rich myelin is being formed. The slow turnover of brain cholesterol is in marked contrast to that in most other organs [1,2]. The mechanistic basis for these differences is unknown, although they are probably a result of the functional isolation of brain and blood cholesterol [3][4][5].According to current concepts, the synthesis and elimination of cholesterol in the adult brain is compartmentalised-astroglial cells are believed to be responsible for the majority of synthesis in the adult brain while they contribute relatively little to brain elimination. The neuron specific cytochrome P450 cholesterol 24-hydroxylase (CYP46A1) is responsible for the elimination of about two thirds of the cholesterol synthesised by the brain [6,7]. Recently it was shown that deletion of this gene led to a reduction in the rate of brain cholesterol synthesis while the level of brain cholesterol was maintained [8]. Due to the importance of this enzyme for brain cholesterol balance we have previously investigated its transcriptional regulation [9], with an expectation that a gene so important for brain cholesterol balance would be subject to complex mechanisms of regulation. Surprisingly we found the opposite-expression of CYP46A1 was insensitive to mechanisms known to regulate the key genes in cholesterol synthesis and elimination, HMGCR and CYP7A1,...

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Section: Cyp7b1mentioning

confidence: 81%

Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors

Shafaati

O’Driscoll

Björkhem

et al. 2009

Biochemical and Biophysical Research Communications

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“…Although the reduction of estrone into 17a-estradiol was reported with 3(17)a-HSD of rabbit kidney and liver, 7) there is no report on the enzyme that catalyzes the reduction of DHEA and its sulfate into the 17a-hydroxymetabolites. In addition, the K m values for DHEA of the two isoforms of mouse 3(17)a-HSD are lower by more than one order of magnitude than those of other DHEA-metabolizing enzymes, such as human 17b-HSD type 5, 33) human 17b-HSD type 1, 34) rat alcohol sulfotransferase, 35) and rat and human 7a-hydroxylase. 36) The K m values for DHEA sulfate of mouse 3(17)a-HSDs are also lower than that of human steroid sulfatase.…”

Section: )mentioning

confidence: 94%

Characterization of Two Isoforms of Mouse 3(17).ALPHA.-Hydroxysteroid Dehydrogenases of the Aldo-Keto Reductase Family

Ishikura

Usami

Nakajima

et al. 2004

Biological & Pharmaceutical Bulletin

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Mouse kidney contains two 3(17)a a-hydroxysteroid dehydrogenases (HSDs) that show essentially the same properties except for their isoelectric points. However, the structural differences and physiological roles of the two enzymes remain unknown. In this study, we have isolated cDNAs for the two 3(17)a a-HSDs from a total RNA sample of mouse kidney by reverse transcription-PCR. The identity of the cDNAs was confirmed by characterization of the recombinant enzymes that showed the same molecular weights, pI values, pH optima, substrate specificity and inhibitor sensitivity as those of the enzymes from mouse kidney. We also found that the recombinant enzymes reduce precursors of neuroactive progesterone derivatives, 5a a-dihydrotestoserone, deoxycorticosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and estrone at low K m values of 0.3-2 m mM. The two enzymes belonged to the aldo-keto reductase (AKR) family, and their 323-amino acid sequences differed only by five amino acids. The sequences of the two isoforms are identical to those of proteins that are predicted to be encoded in a gene for AKR1C21 in the database of the mouse genome. However, the mRNAs for the two isoforms were expressed in mouse kidney and other tissues, in which their expression levels were different. The results indicate an important role of 3(17)a a-HSD in controlling the concentrations of various steroid hormones in the mouse tissues, and suggest the existence of two genes for the two isoforms of the enzyme.

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“…The activity of this enzyme has recently been demonstrated in the human brain of both sexes. It is significantly higher in the cerebral cortex than in the subcortical white matter from biopsies (Steckelbroeck et al, 2002). The biological significance of 7␣-OH-DHEA and ADIOL in the brain still needs to be elucidated.…”

Section: Steroids In the Aging Nervous System: The Endocrine Glands Amentioning

confidence: 96%

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

Schumacher

Weill-Engerer

Lière

et al. 2003

Progress in Neurobiology

272

171

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Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the ␤-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to 5-androstene-3␤,17␤-diol and to 7␣-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of ␤-amyloid deposits.

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

Cited by 59 publications

References 63 publications

Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors

Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors

Characterization of Two Isoforms of Mouse 3(17).ALPHA.-Hydroxysteroid Dehydrogenases of the Aldo-Keto Reductase Family

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

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