Chapter 11 - Steroidogenic Enzymes in the Brain: Morphological Aspects
Introduction
The steroid hormones exert a determinant role in brain development while regulating various physiological functions such as locomotion, feeding, sexual behaviors, learning and memory (for a review, see McEwen, 1994). It has been long believed that the steroids acting on the brain were originating from steroidogenic glands, including gonads, adrenal cortex and plasma. In the early eighties, it was shown that the brain is capable of de novo biosynthesis of steroids. The first clue of neurosteroidogenesis came from the observations that pregnenolone, dehydroepiandrosterone (DHEA), and their sulphate derivatives accumulate in the brain of castrated and adrenalectomized rats (Corpéchot et al., 1981). Moreover, Robel et al., (1986) showed that circadian variations of steroid concentrations in brain tissue are not synchronized with those of steroids measured in peripheral blood. As a result, the term neurosteroids was proposed to designate the steroids synthesized in the brain, either de novo from cholesterol or by in situ metabolism of blood-borne precursors (Baulieu, 1997, Robel and Baulieu, 1985). The concept of neurosteroidogenesis has been subsequently supported by morphological data showing the occurrence of steroidogenic enzymes or their mRNAs by immunohistochemistry and in situ hybridization, respectively (Do Rego et al., 2007, Dupont et al., 1994, Le Goascogne et al., 1987, Mellon and Vaudry, 2001, Mensah-Nyagan et al., 1994, Pelletier et al., 2003, Mensah-Nyagan et al., 1999, Pelletier et al., 2007, Robel and Baulieu, 1985). The morphological approach has largely contributed to accurately determine the brain areas involved in the biosynthesis and metabolism of active neurosteroids as well as to identify the cell type (neurons/glial cells) expressing the different enzymes.
The aim of this chapter is to summarize the current research about the expression of steroidogenic enzymes in the brain with special emphasis on their cellular localization.
Section snippets
Cytochrome P450 side-chain cleavage
The first step in the synthesis of all steroid hormones is the conversion of cholesterol to pregnenolone by a mitochondrial enzyme, cytochrome P450 side-chain cleavage (scc) (Lieberman et al., 1984). This enzyme was first observed by Le Goascogne et al. (1987) who detected by immunocytochemistry the presence of immunoactive glial cells in the white matter throughout the rat brain. P450 scc protein has also been detected by Western blot analysis in the cerebellum and by immunochemistry in
3β-Hydroxysteroid dehydrogenase
3β-Hydroxysteroid dehydrogenase (3β-HSD) is a membrane-bound mitochondrial enzyme that catalyzes the conversion of Δ5-3β-hydroxysteroid into Δ4-3β-ketosteroids, leading to the formation of progesterone from pregnenolone and androstenedione from DHEA. In human, two isoforms of 3β-HSD have been characterized: type 1 is mainly expressed in the placenta, but also found in the skin and mammary gland (Luu The et al., 1989, Rheaume et al., 1991) while type 2 is predominantly expressed in the adrenal
Cytochrome P450C17
Cytochrome P450C17, also termed 17α-hydroxylase/C17.20 lyase, catalyzes the hydroxylation of C21 steroids (pregnenolone, progesterone) into C19 steroids (DHEA and androstenedione, respectively).
Although the presence of DHEA and androstenedione in the brain is well documented (Akwa et al., 1991, Corpechot et al., 1981, Jo et al., 1989, Lanthier and Patwardhan, 1986, Matsunaga et al., 2001, Mensah-Nyagan et al., 1996, Robel et al., 1986, Soma et al., 2004), the biosynthetic pathways leading to
17β-Hydroxysteroid dehydrogenase
The enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) catalyzes the interconversion between the active and inactive forms of specific steroidal hormones in the final steps of their biosynthesis (Labrie et al., 2000). They are named according to their ability to catalyze oxidation or reduction of the 17-hydroxy or 17-keto functions of specific physiologically relevant steroids. Up to now, 15 types of 17β-HSDs are reported in vertebrates (Moeller and Adamski, 2009). With the exception of
5α-Reductase
The enzyme 5α-reductase catalyzes the transformation of progesterone, T and 11-deoxycorticosterone into 5α-dihydroprogesterone, 5α-dihydrotestosterone and 5α-dihydrodeoxycorticosterone, respectively. Two 5α-reductase isozymes encoded by two distinct genes, designated type 1 and type 2, have been identified in rodents (Berman and Russell, 1993, Mahendroo et al., 1996, Normington and Russell, 1992), monkey (Levy et al., 1995) and human (Andersson et al., 1991, Labrie et al., 1992, Russell and
3α-Hydroxysteroid dehydrogenase
3α-Hydroxysteroid dehydrogenase (3α-HSD) is a bifunctional enzyme that interconverts, in a reversible manner, the 5α-reduced steroids (5α-DHT and 5α-dihydroprogesterone (5α-DHP) into 3α-androstanediol and 3α,5α-tetrahydroprogesterone, respectively). 3α-HSD also catalyzes the reversible conversion of dihydrodeoxycorticosterone into tetrahydrodeoxycorticosterone. In humans, multiple cDNAs encoding various proteins structurally related to 3α-HSD have been reported (Qin et al., 1993). However, to
20α-Hydroxysteroid dehydrogenase
The enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD) catalyzes the conversion of progesterone into its inactive form, 20α-hydroxyprogesterone (Zhang et al., 2000). In the brain of several species, conversion of progesterone into 20α-reduced metabolites has been reported, indicating that some brain areas have 20α-HSD activity (Karavolas and Hodges, 1990). Recently, with a cRNA probe that has been successfully used to localize 20α-HSD by in situ hybridization in a variety of mouse tissues (
Cytochrome P450 aromatase
Cytochrome P450 aromatase (P450arom) catalyzes the conversion of C19 androgens (androstenedione and testosterone) into C18 estrogens (estrone and estradiol, respectively). The presence of P450arom mRNA in the brain of mammals has been demonstrated by RT-PCR and in situ hybridization histochemistry (Harada and Yamada, 1992, Hojo et al., 2004, Lephart et al., 1992). In rat and mouse, intense expression of the P450arom gene occurs in the cerebral cortex, medial preoptic nucleus, bed nucleus of the
11β-Hydroxysteroid dehydrogenase
The interconversion of glucocorticoids from their inactive (11-dehydrocorticosterone, cortisone) to their active forms (corticosterone, cortisol) is catalyzed by the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) in specific tissues. Molecular cloning of the cDNAs encoding 11β-HSD revealed the existence of two isoforms of the enzyme, 11β-HSD type 1 and type 2, in humans and rodents (Tannin et al., 1991, Zhou et al., 1995). 11β-HSD type 1 is a bidirectional enzyme, predominantly displaying
Conclusion
Since the first observation by Beaulieu and his collaborators (Corpéchot et al., 1981) that some hormonal steroids were in higher concentrations in the brain than in blood, there have been a large number of reports on the expression of steroidogenic enzymes in the brain. So far, most of the enzymes involved in the biosynthesis and metabolism of all the categories of steroid hormones (sex steroids and glucocorticoids) have been found to be expressed in the brain of many representative species of
References (138)
- et al.
Neurosteroids: biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain
The Journal of Steroid Biochemistry and Molecular Biology
(1991) - et al.
Micromethod for the determination of 3-beta-HSD activity in cultured cells
The Journal of Steroid Biochemistry
(1989) Neurosteroids: a novel function of the brain
Psychoneuroendocrinology
(1998)- et al.
Aromatase-immunoreactivity is localised specifically in neurones in the developing mouse hypothalamus and cortex
Brain Research
(1994) - et al.
Identification of radioactivity in cell nuclei from brain, pituitary gland and genital tract of male rhesus monkeys after the administration of [3h]testosterone
The Journal of Steroid Biochemistry
(1989) - et al.
Immunohistochemical localization and biological activity of 3beta-hydroxysteroid dehydrogenase and 5alpha-reductase in the brain of the frog, Rana esculenta, during development
Journal of Chemical Neuroanatomy
(2010) - et al.
Steroid metabolism in the mammalian brain: 5alpha-reduction and aromatization
Biology of Reproduction
(1997) - et al.
Neurosteroids: biosynthesis and function of these novel neuromodulators
Frontiers in Neuroendocrinology
(2000) - et al.
Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides
Frontiers in Neuroendocrinology
(2009) - et al.
Localization of 3 beta-hydroxysteroid dehydrogenase in rat brain as studied by in situ hybridization
Molecular and Cellular Neuroscience
(1994)
Progesterone-transforming enzyme activity in the hypothalamus of the male rat
The Journal of Steroid Biochemistry and Molecular Biology
A key enzyme in the biosynthesis of neurosteroids, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD), is expressed in rat brain
Brain Research. Molecular Brain Research
Estrogen synthesis in the brain--role in synaptic plasticity and memory
Molecular and Cellular Endocrinology
The role of 11beta-hydroxysteroid dehydrogenases in the brain
Molecular and Cellular Endocrinology
Seasonal changes in neurosteroid concentrations in the amphibian brain and environmental factors regulating their changes
Brain Research
Diminished aromatase immunoreactivity in the hypothalamus, but not in the basal forebrain nuclei in alzheimer’s disease
Neurobiology of Aging
Testosterone metabolism in target tissues. Hypothalamic and pituitary tissues of the adult rat and human fetus, and the immature rat epiphysis
Steroids
Aromatase- (estrogen synthetase) immunoreactive neurons in the rat septal area. A light and electron microscopic study
Brain Research
Aromatase immunoreactivity in the rat brain: gonadectomy-sensitive hypothalamic neurons and an unresponsive “limbic ring” of the lateral septum-bed nucleus-amygdala complex
The Journal of Steroid Biochemistry and Molecular Biology
11beta-hydroxysteroid dehydrogenase functions reversibly as an oxidoreductase in the rat hippocampus in vivo
The Journal of Steroid Biochemistry and Molecular Biology
Pregnenolone, dehydroepiandrosterone, and their sulfate and fatty acid esters in the rat brain
Steroids
Gene expression of progesterone receptor isoforms in the rat brain
Hormones and Behavior
Histological and metabolism analysis of P450 expression in the brain
Methods in Enzymology
Distribution of 3 alpha-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans
The Journal of Steroid Biochemistry and Molecular Biology
Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases
The Journal of Biological Chemistry
Age- and region-specific expressions of the messenger RNAs encoding for steroidogenic enzymes p450scc, P450c17 and 3beta-HSD in the postnatal rat brain
Brain Research
Characterization of two mRNA species encoding human estradiol 17 beta-dehydrogenase and assignment of the gene to chromosome 17
The Journal of Steroid Biochemistry
Role of 17 beta-hydroxysteroid dehydrogenases in sex steroid formation in peripheral intracrine tissues
Trends in Endocrinology and Metabolism
Sex steroids and 5-en-3 beta-hydroxysteroids in specific regions of the human brain and cranial nerves
The Journal of Steroid Biochemistry
Brain 5alpha-reductase: cellular, enzymatic, and molecular perspectives and implications for biological function
Molecular and Cellular Neuroscience
A review of brain aromatase cytochrome P450
Brain Research Brain Research Reviews
Brain aromatase cytochrome P-450 messenger RNA levels and enzyme activity during prenatal and perinatal development in the rat
Brain Research Molecular Brain Research
Cloning, expression and functional characterization of type 1 and type 2 steroid 5 alpha-reductases from cynomolgus monkey: comparisons with human and rat isoenzymes
The Journal of Steroid Biochemistry and Molecular Biology
Distribution of 17 beta-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues
The Journal of Steroid Biochemistry and Molecular Biology
Expression and localization of cytochrome P450 17α-hydroxylase/c17, 20-lyase in the avian brain
Brain Res
3Beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase mRNA expression in rat brain: effect of pseudopregnancy and traumatic brain injury
The Journal of Steroid Biochemistry and Molecular Biology
The 5alpha-reductase in the central nervous system: expression and modes of control
The Journal of Steroid Biochemistry and Molecular Biology
Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain
Brain Research
Biosynthesis of neurosteroids and regulation of their synthesis
International Review of Neurobiology
Integrated view on 17beta-hydroxysteroid dehydrogenases
Molecular and Cellular Endocrinology
Metabolism of steroids in the brain: a new insight into the role of 5alpha-reductase and aromatase in brain differentiation and functions
The Journal of Steroid Biochemistry and Molecular Biology
Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions
The Journal of Biological Chemistry
Immunocytochemical localization of 5 alpha-reductase in rat brain
Molecular and Cellular Neuroscience
Immunocytochemical localization of type I 17 beta-hydroxysteroid dehydrogenase in the rat brain
Brain Research
Localization and glucocorticoid regulation of 11beta-hydroxysteroid dehydrogenase type 1 mRNA in the male mouse forebrain
Neuroscience
Localization of 20alpha-hydroxysteroid dehydrogenase mRNA in mouse brain by in situ hybridization
Brain Research Molecular Brain Research
Structure-function relationships in 3alpha-hydroxysteroid dehydrogenases: a comparison of the rat and human isoforms
The Journal of Steroid Biochemistry and Molecular Biology
Estrogen enhancement of ca-, mg-, and ca-mg-stimulated adenosine triphosphatase activity in the chick shell gland
General and Comparative Endocrinology
Distribution of aromatase cytochrome P450 messenger ribonucleic acid in adult rhesus monkey brains
Biology of Reproduction
Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis
Proceedings of the National Academy of Sciences of the United States of America
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