A key enzyme in the biosynthesis of neurosteroids, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3β-HSD), is expressed in rat brain

Guennoun, Rachida; Rj, Fiddes; Gouézou, M.; Lombès, Marc; Ee, Baulieu

doi:10.1016/0169-328x(95)00016-l

Cited by 198 publications

(129 citation statements)

References 38 publications

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“…3␤-Hydroxysteroid dehydrogenase/⌬ 5 -⌬ 4 isomerase (3␤-HSD), which plays a role in the synthesis of neurosteroids, was expressed at the mRNA and protein levels in rat brain, at a particularly high level in the cerebellum, and an enzymatic activity for conversion of 3␤-hydroxy-⌬ 5 derivatives into the corresponding ⌬ 4 -3-keto steroids was demonstrated (21). In hepatocytes, bile acids bind to cytosolic bile acid binding protein, which is a member of the monomeric reductase gene family and has dihydrodiol dehydrogenase activity but does not have activity toward bile acids in human (22).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…This enzyme is found in neurons and in glia rat brains (Carre et al, 2001;Guennoun et al, 1995;Ibanez et al, 2003;Kohchi et al, 1998;Ukena et al, 1999b). While this enzyme is found from birth to adulthood, whole brain expression of 3ßHSD mRNA decreases throughout life.…”

Section: General Overviewmentioning

confidence: 99%

“…Consistent with this decline in 3ß HSD mRNA, concentrations of hippocampal pregnenolone and progesterone are highest on the day of birth and lower thereafter. 3ßHSD is associated with white matter (Sanne and Krueger, 1995) and gray matter (Dupont et al, 1994;Guennoun et al, 1995;Ukena et al, 1999a), and enzyme activity is found in vitro in glial cells (Akwa et al, 1993;Jung-Testas et al, 1989). Progesterone may also be metabolized further by the enzyme 5alpha reductase, to 5α-dihydroprogesterone, which can also be metabolized by the reversible enzyme 3α hydroxysteroid dehydrogenase, to the neurosteroid allopregnanolone (Compagnone and Mellon, 2000).…”

Section: General Overviewmentioning

confidence: 99%

Neurosteroid regulation of central nervous system development

Mellon

2007

Pharmacology & Therapeutics

186

117

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Neurosteroids are a relatively new class of neuroactive compounds, brought to prominence in the past two decades. Despite knowing of their presence in the nervous system of various species for over twenty years and knowing of their functions as GABA A and NMDA ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of four distinct neurosteroids -pregnenolone, progesterone, allopregnanolone and dehydroepiandrosterone.

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“…Oligodendrocytes preferentially synthesize pregnenolone, and neurons aromatize circulating androgens to estrogens. (Guennoun et al, 1995;Jung-Testas et al, 1989;Jung-Testas et al, 1991;Kohchi et al, 1998;Micevych et al, 2007;Robel, 1995;Sanne et al, 1995;Zwain et al, 1999),…”

Section: Regulation Of Neurosteroidogenesismentioning

confidence: 99%

“…The brain has always been considered a target for sex steroid hormones produced by peripheral steroidogenic organs, the gonads and the adrenal glands, but it is now well accepted that the brain synthesizes neurosteroids de novo, and converts circulating steroids to neuroactive steroids (Corpechot et al, 1981;Guennoun et al, 1995;Jung-Testas et al, 1989;Jung-Testas et al, 1991;Kohchi et al, 1998;Micevych et al, 2007;Robel, 1995;Sanne and Krueger, 1995;Sinchak et al, 2003;Zwain and Yen, 1999). Regardless of their origin, steroids affect brain function through actions at their cognate receptors, or by affecting receptors whose primary transmitter is not a steroid (e.g., GABA receptors).…”

Section: Introductionmentioning

confidence: 99%

Estradiol regulation of progesterone synthesis in the brain

Micevych

Sinchak

2008

Molecular and Cellular Endocrinology

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Steroidogenesis is now recognized as a global phenomenon in the brain, but how it is regulated and its relationship to circulating steroids of peripheral origin have remained more elusive issues. Neurosteroids, steroids synthesized de novo in nervous tissue, have a large range of actions in the brain, but it is only recently that the role of neuroprogesterone in the regulation of arguably the quintessential steroid dependent neural activity, regulation of the reproduction has been appreciated. Circuits involved in controlling the LH surge and sexual behaviors were thought to be influenced by estradiol and progesterone synthesized in the ovary and perhaps the adrenal. It is now apparent that estradiol of ovarian origin regulates the synthesis of neuroprogesterone, and it is the locally produced neuroprogesterone that is involved in the initiation of the LH surge and subsequent ovulation. In this model, estradiol induces the transcription of progesterone receptors while stimulating synthesis of neuroprogesterone. Although the complete signaling cascade has not been elucidated, many of the features have been characterized. The synthesis of neuroprogesterone occurs primarily in astrocytes and requires the interaction of membrane associated estrogen receptor-α with metabotropic glutamate receptor-1a. This G protein-coupled receptor activates a phospholipase C that in turn increases inositol trisphosphate (IP 3 ) levels mediating the release of intracellular stores of Ca 2+ via an IP 3 receptor gated Ca +2 channel. The large increase in free cytoplasmic Ca 2+ ([Ca 2+ ] i ) stimulates the synthesis of progesterone, which can then diffuse out of the astrocyte and activate estradiol-induced progesterone receptors in local neurons to trigger the neural cascade to produce the LH surge. Thus, it is a cooperative action of astrocytes and neurons that is needed for estrogen positive feedback and stimulation of the LH surge.

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A key enzyme in the biosynthesis of neurosteroids, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3β-HSD), is expressed in rat brain

Cited by 198 publications

References 38 publications

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

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

Neurosteroid regulation of central nervous system development

Estradiol regulation of progesterone synthesis in the brain

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