Neurosteroid metabolism. 7<i>α</i>-Hydroxylation of dehydroepiandrosterone and pregnenolone by rat brain microsomes

Akwa, Yvette; Morfin, Robert; Röbel, P; Baulieu, Étienne Émile

doi:10.1042/bj2880959

Cited by 163 publications

(87 citation statements)

References 23 publications

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“…The verified occurrence of DHEA 7a-hydroxylase and DHEA 17-ketosteroid reductase activity in the human temporal lobe (Figs 2, 4 and 5) is in accordance with results obtained from rodent brain tissue experiments (Akwa et al 1992;Doostzadeh et al 1997;Rose et al 1997;Fig. 6).…”

Section: Discussionsupporting

confidence: 89%

“…Within the rodent brain, DHEA is also known to be converted into 7b-hydroxy-DHEA (Akwa et al 1992;Doostzadeh et al 1997). According to this, we observed the formation of low amounts of a third polar metabolite when investigating mouse brain tissue homogenates (Fig.…”

Section: Discussionsupporting

confidence: 59%

“…The kinetic characterization of the recombinant rat protein revealed a K M -value of 13.6 lM (Rose et al 1997). Microsomal rat brain 7a-hydroxylase activity with DHEA as the substrate showed a K M -value of 13.8 lM and a pH optimum of 7.8 (Akwa et al 1992). According to these results, the human cerebral DHEA 7a-hydroxylase is obviously also a membrane-associated protein with a sharp pH optimum between 7.5 and 8.0 (Figs 3a and c).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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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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“…DHEA, pregnenolone and 5-Adiol are readily hydroxylated at C7 (Akwa et al, 1992;Lathe, 2002;Lardy, 2003). Moreover, these 7 -11 hydroxy-and 7 -hydroxy-steroids can be oxidized to 7-oxo-steroids [ Figure 4].…”

Section: A Paradox the Er And Not The Pr Is Most Ancient: What Was Tmentioning

confidence: 99%

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Baker

2004

Molecular and Cellular Endocrinology

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Abstract. Receptors for the adrenal and sex steroids arose by a series of gene duplications from an ancestral nuclear receptor in a primitive vertebrate, at least 540 million years ago. Sequence analysis indicates many steroidogenic and steroid-inactivating enzymes, including cytochrome P450s and hydroxysteroid dehydrogenases, arose at the same time. The estrogen receptor (ER) appears to be the ancestral steroid receptor. Initially, the redundant duplicated ER had a low specificity for its new ligand. This raises the question: "How was specificity for responses to different steroids regulated early in the evolution of steroid receptors?" Selective expression of these steroid-metabolizing enzymes provided specificity for different steroid responses in primitive vertebrates. 17 -hydroxysteroid dehydrogenase-type 1 (17 -HSD-type 1) and 17 -HSD-type 2, which preferentially catalyze the reduction and oxidation at C17 of androgens and estrogens, respectively, provide an example of this mechanism. Selective expression of either 17 -HSD-type 1 or 17 -HSD-type 2 can regulate synthesis or inactivation of androgens or estrogens in specific cells.Steroids also were important in the evolution of land animals, which began about 400 million years ago.Steroidogenic and steroid-inactivating enzymes were recruited to regulate steroid-mediated responses as organ function became more complex. For example, in the kidney 11 -HSD-type 2 prevents binding of glucocorticoids to the mineralocorticoid receptor, which is crucial for aldosterone-mediated regulation of electrolyte transport in the distal tubule. We propose that 5 steroids, such as dehydroepiandrosterone and its metabolites, were the ligands for the ancestral ER. Understanding the actions of 5 steroids in amphioxus and lamprey may shed light on adrenarche and neurosteroid actions in humans.

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“…24-Hydroxylated cholesterol, which is a possible precursor of 3 ␤ -hydroxy-5-cholenoic acid, has been detected at very high levels in the brain (7). In addition, Akwa et al (8) have demonstrated that conversion of two neurosteroids, dehydroepiandrosterone and pregnenolone, into the corresponding 7 ␣ -hydroxylated derivatives occurs in rat brain microsomal fractions. In addition, in an older publication, 3 H-labeled 3 ␤ -hydroxy-5-cholenoic acid was metabolized into lithocholic acid when incubated with normal guinea pig brain preparations (9).…”

mentioning

confidence: 99%

Bioconversion of 3β-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems

Mano

Sato

Nagata

et al. 2004

Journal of Lipid Research

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We have previously demonstrated that the rat brain contains three unconjugated bile acids, and chenodeoxycholic acid (CDCA) is the most abundantly present in a tight protein binding form. The ratio of CDCA to the other acids in rat brain tissue was significantly higher than the ratio in the peripheral blood, indicating a contribution from either a specific uptake mechanism or a biosynthetic pathway for CDCA in rat brain. In this study, we have demonstrated the existence of an enzymatic activity that converts 3 ␤ -hydroxy-5-cholenoic acid into CDCA in rat brain tissue. To distinguish marked compounds from endogenous related compounds, 18 O-labeled 3 ␤ -hydroxy-5-cholenoic acid, 3 ␤ ,7 ␣ -dihydroxy-5-cholenoic acid, and 7 ␣ -hydroxy-3-oxo-4-cholenoic acid were synthesized as substrates for in vitro incubation studies. The results clearly suggest that 3 ␤ -hydroxy-5-cholenoic acid was converted to 3 ␤ ,7 ␣ -dihydroxy-5-cholenoic acid by microsomal enzymes. The 7 ␣ -hydroxy-3-oxo-4-cholenoic acid was produced from 3 ␤ ,7 ␣ -dihydroxy-5-cholenoic acid by the action of microsomal enzymes, and ⌬ 4 -3-oxo acid was converted to CDCA by cytosolic enzymes. These findings indicate the presence of an enzymatic activity that converts 3 ␤ -hydroxy-5-cholenoic acid into CDCA in rat brain tissue. Furthermore, this synthetic pathway for CDCA may relate to the function of 24 S -hydroxycholesterol, which plays an important role in cholesterol homeostasis in the body.

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Neurosteroid metabolism. 7α-Hydroxylation of dehydroepiandrosterone and pregnenolone by rat brain microsomes

Cited by 163 publications

References 23 publications

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

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

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Bioconversion of 3β-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems

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