Molecular Endocrinology of Hydroxysteroid Dehydrogenases*

Penning, T.M.

doi:10.1210/edrv.18.3.0302

Cited by 204 publications

(221 citation statements)

References 183 publications

(177 reference statements)

Supporting

Mentioning

218

Contrasting

Order By: Relevance

“…Multiple forms of the 3␣-hydroxysteroid dehydrogenase enzyme exist, some of which oxidize and some of which reduce the oxygen at carbon 3 of 5␣-reduced steroids (21). To examine 5␣-adiol metabolism in various tammar pouch young tissues, minces of testes and urogenital tracts were incubated in vitro with radioactive testosterone, DHT, or 5␣-adiol, and the metabolites were separated by TLC and assayed by scintillation spectroscopy (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…First, it could work via a typical nuclear steroid hormone receptor. However, 5␣-adiol binds to the androgen receptor with a much lower affinity than DHT (21), and no evidence has been reported to date for a specific 5␣-adiol receptor. Second, at the cell surface in some androgen target tissues 5␣-adiol acts in combination with sex hormonebinding globulin to enhance cAMP production and to activate secondarily the androgen receptor (24).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prostate formation in a marsupial is mediated by the testicular androgen 5α-androstane-3α,17β-diol

Shaw

Renfree

Leihy

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

100

View full text Add to dashboard Cite

Development of the male urogenital tract in mammals is mediated by testicular androgens. It has been tacitly assumed that testosterone acts through its intracellular metabolite dihydrotestosterone (DHT) to mediate this process, but levels of these androgens are not sexually dimorphic in plasma at the time of prostate development. Here we show that the 3␣-reduced derivative of DHT, 5␣-androstane-3␣,17␤-diol (5␣-adiol), is formed in testes of tammar wallaby pouch young and is higher in male than in female plasma in this species during early sexual differentiation. Administration of 5␣-adiol caused formation of prostatic buds in female wallaby pouch young, and in tissue minces of urogenital sinus and urogenital tubercle radioactive 5␣-adiol was converted to DHT, suggesting that circulating 5␣-adiol acts through DHT in target tissues. We conclude that circulating 5␣-adiol is a key hormone in male development. I n all mammalian species testicular androgens control three aspects of male phenotypic development-conversion of the wolffian ducts into the epididymis, vas deferens, and seminal vesicles; formation of the male urethra and prostate; and formation of the phallus (1). Studies in animals and humans with mutations in the genes that encode the androgen receptor or steroid 5␣-reductase 2 indicate that testosterone virilizes the wolffian ducts and that 5␣-reduced androgens are essential for formation of the prostate and phallus (1). Because virilization occurs during early fetal development in eutherian mammals, it has not been possible to measure androgens in the circulation when virilization begins.Marsupial mammals offer an advantage for studying male phenotypic development, which takes place after birth when the young are easily accessible in the pouch and over a longer period than in the eutherian, so that it is possible to study the various aspects of phenotypic development individually (2). Virilization of the urogenital tract in the male marsupial pouch young is similar to that in eutherian fetuses, except that formation of the scrotum in marsupials is androgen-independent (2-6). This process has been examined in detail in one marsupial species, the tammar wallaby, Macropus eugenii, in which formation of the prostate begins in the urogenital sinus at around day 20 postpartum (5), whereas virilization of the penis commences around day 100 (6). Testosterone concentrations in the testes increase before prostate formation begins (7), and prostate development can be prevented by administration of the steroid 5␣-reductase inhibitor finasteride (8), which blocks the formation of dihydrotestosterone (DHT), or of the androgen receptor inhibitor flutamide (9), which prevents the actions of both testosterone and DHT. Administration of large amounts of testosterone (5) or transplantation of testes to female pouch young (10) causes prostate development, whereas castration of 10-day-old male pouch young prevents formation of the prostate and penis (10).Despite the wealth of evidence for a crucial role of 5␣-reduced androge...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prostate formation in a marsupial is mediated by the testicular androgen 5α-androstane-3α,17β-diol

Shaw

Renfree

Leihy

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

100

View full text Add to dashboard Cite

show abstract

“…However, it should be emphasized that discrete isofroms may be involved in regulating ligand access to nuclear receptors. AKRs that have hydroxysteroid dehydrogenase activity can either form or eliminate active steroid hormone in target tissues and therefore may regulate the occupancy and ^raws-activation of steroid receptors (54). A similar case could be made for AKRs that have prostaglandin reductase activity since they may regulate ligand access to PPARy receptors (55).…”

Section: Future Directionsmentioning

confidence: 99%

Introduction and Overview of the Aldo-Keto Reductase Superfamily

Penning

2003

ACS Symposium Series

Self Cite

View full text Add to dashboard Cite

Aldo-Keto Reductases (AKRs) are a rapidly growing gene superfamily involved in the formation of hyperosmotic sugars, which can contribute to diabetic complications. They also metabolize reactive aldehydes, prostaglandins, steroid hormones, chemical carcinogens and drugs. These enzymes (>115) are generally monomeric, cytosolic, NAD(P)Hdependent-oxidoreductases, that share high sequence identity -(<40%) and similar three-dimensional-structures e.g., (α/β) 8 -barrels and belong to 14 families. For a complete listing of the 14 families visit: www.med.upenn.edu/akr. AKRs detoxify endogenous toxicants, e.g., cytotoxic/mutagenic bifunctional electrophiles derived from the decomposition of lipid hydroperoxides. AKRs also metabolize exogenous toxic substances. They play a role in tobacco-carcinogenesis since they catalyze the detoxication of nicotine derived nitrosaminoketones and activate polycyclic aromatic trans-dihydrodiols to yield reactive and redox active ortho-quinones. Discrete isozymes also detoxify mycotoxin metabolites, e.g., aflatoxin dialdehyde and protect against hepatocellular carcinoma. The aflatoxin reductases are induced by cancer chemopreventive agents, e.g., ethoxyquin. Evidence is mounting that AKRs are stress regulated genes and play a central role in the cellular response to osmotic, electrophilic and oxidative stress.

show abstract

“…Dihydrotestosterone is inactivated by NADPH-dependent cytosolic 3␣-hydroxysteroid dehydrogenases, which reduce dihydrotestosterone to adiol (reviewed in Ref. 34). The presence of the NAD ϩ -dependent 3␣-hydroxysteroid dehydrogenase in prostate explains the so-called back reaction, in which adiol is oxidized back to dihydrotestosterone.…”

Section: Human Microsomal Nadmentioning

confidence: 99%

cDNA Cloning and Characterization of a New Human Microsomal NAD+-dependent Dehydrogenase that Oxidizes All-trans-retinol and 3α-Hydroxysteroids

Gough

VanOoteghem

Sint

et al. 1998

Journal of Biological Chemistry

108

118

View full text Add to dashboard Cite

We report the cDNA sequence and catalytic properties of a new member of the short chain dehydrogenase/ reductase superfamily. The 1134-base pair cDNA isolated from the human liver cDNA library encodes a 317-amino acid protein, retinol dehydrogenase 4 (RoDH-4), which exhibits the strongest similarity with rat alltrans-retinol dehydrogenases RoDH-1, RoDH-2, and RoDH-3, and mouse cis-retinol/androgen dehydrogenase (<73% identity). The mRNA for RoDH-4 is abundant in adult liver, where it is translated into RoDH-4 protein, which is associated with microsomal membranes, as evidenced by Western blot analysis. Significant amounts of RoDH-4 message are detected in fetal liver and lung. Recombinant RoDH-4, expressed in microsomes of Sf9 insect cells using BacoluGold Baculovirus system, oxidizes all-trans-retinol and 13-cis-retinol to corresponding aldehydes and oxidizes the 3␣-hydroxysteroids androstane-diol and androsterone to dihydrotestosterone and androstanedione, respectively. NAD ؉ and NADH are the preferred cofactors, with apparent K m values 250 -1500 times lower than those for NADP ؉ and NADPH. All-trans-retinol and 13-cis-retinol inhibit RoDH-4 catalyzed oxidation of androsterone with apparent K i values of 5.8 and 3.5 M, respectively. All-transretinol bound to cellular retinol-binding protein (type I) exhibits a similar K i value of 3.6 M. Unliganded cellular retinol-binding protein has no effect on RoDH activity. Citral and acyclic isoprenoids also act as inhibitors of RoDH-4 activity. Ethanol is not inhibitory. Thus, we have identified and characterized a sterol/retinol-oxidizing short chain dehydrogenase/reductase that prefers NAD ؉ and recognizes all-trans-retinol as substrate. RoDH-4 can potentially contribute to the biosynthesis of two powerful modulators of gene expression: retinoic acid from retinol and dihydrotestosterone from 3␣-androstane-diol.Short chain alcohol dehydrogenases/reductases are either cytosolic or membrane-bound enzymes with a subunit molecular mass of 25-35 kDa that utilize a vast variety of substrates, including steroids and prostaglandins (1). Recently, this family of enzymes has expanded to include the retinol-oxidizing dehydrogenases (2-6). Retinol dehydrogenases are involved in the biosynthesis of all-trans-retinoic acid, the activating ligand for a family of nuclear receptors (7). All-trans-retinoic acid is produced from all-trans-retinol in two oxidative steps: all-transretinol is oxidized to all-trans-retinal and then further to alltrans-retinoic acid. Retinol dehydrogenases catalyze the ratelimiting step: the oxidation of retinol to retinaldehyde (8). Although the effects of retinoic acid on gene transcription and regulation have been intensively studied during the last decade, the exact enzymes that synthesize this morphogen and the mechanisms that regulate its production in tissues are not fully understood. Enzymatic activity capable of oxidizing retinol to retinaldehyde is readily detected in the cytosolic and microsomal fractions of total cell homogenates (9). The cytosol...

show abstract

Molecular Endocrinology of Hydroxysteroid Dehydrogenases*

Cited by 204 publications

References 183 publications

Prostate formation in a marsupial is mediated by the testicular androgen 5α-androstane-3α,17β-diol

Prostate formation in a marsupial is mediated by the testicular androgen 5α-androstane-3α,17β-diol

Introduction and Overview of the Aldo-Keto Reductase Superfamily

cDNA Cloning and Characterization of a New Human Microsomal NAD+-dependent Dehydrogenase that Oxidizes All-trans-retinol and 3α-Hydroxysteroids

Contact Info

Product

Resources

About