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PubMedDate not supplied

17 beta-hydroxysteroid oxidoreductases of human fetal and adult tissues: immunological cross-reactivity with an anti-human placental cytosolic 17 beta-hydroxysteroid oxidoreductase antibody.

To determine whether the immunological determinants of human placental 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR) were present in 17 beta-HSORs of tissues of the human fetus and adult and of various non-human cells maintained in culture, western immunoblot analysis was conducted by use of a polyclonal antibody directed against determinants of the placental cytosolic enzyme. Tissues and cells were evaluated for the presence of immunocross-reactive proteins with a relative molecular mass (Mr) similar to that of placental 17 beta-HSOR (approximately 34,000). By use of homogenates of human fetal tissues, immunostaining of 17 beta-HSORs of Mr approximately 34 kDa was detected in trophoblast, fetal adrenal neocortex, fetal zone of the adrenal gland, liver, intestine, kidney, brain, lung, skin, heart, spleen, pancreas, chorion laeve, and, occasionally, amnion. Immunostaining at Mr approximately 34 kDa also was demonstrated by use of cytosolic preparations of fetal tissues and, in some cases, by use of unwashed microsomal fractions; this protein was either absent or present in almost undetectable amounts in washed microsomes, except for placenta and fetal brain. Immunostaining at approximately 34 kDa was demonstrated occasionally in decidua of pregnant women by use of homogenates, but was not detected in endometrium or myometrium of non-pregnant women, testis of an adult man, mouse and rat Leydig tumour cells, mouse and rat adrenal tumour cells, and normal bovine adrenocortical cells.

Adult↗
PubMed1996

17 beta-Hydroxysteroid dehydrogenase activity correlates with the type-2 17 beta-hydroxysteroid dehydrogenase mRNA abundance in human meningioma tumors.

Benign meningioma tumors possess significant levels of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity. Two different 17 beta-HSDs were discovered in human placenta: one highly estrogen specific and using NADP+/NADPH as cofactors (type-1 17 beta-HSD), and a second one that utilizes both androgens and estrogens as substrates with NAD+/NADH (type-2 17 beta-HSD). Recently, two further human 17 beta-HSDs were isolated. A testis-specific 17 beta-HSD (type-3 17 beta-HSD) favors the reduction of delta 4-androstenedione to testosterone, and a ubiquitously expressed type-4 17 beta-HSD preferentially catalyzes the oxidation of estradiol and delta 5-androstenediol. In this study we characterize the expression levels of different types of 17 beta-HSD in a wide series of tumors. Using the Northern blotting method we show that type-1, -3, and -4 17 beta-HSDs are not detectable in meningiomas. In contrast, the type-2 17 beta-HSD RNA is present in 6 of 17 meningiomas and its abundance is directly correlated with estrogenic 17 beta-HSD activity (r2 = 0.74). The presence of type-2 17 beta-HSD is also demonstrated by in situ hybridization. RT-PCR and Western blots show that type-4 17 beta-HSD is also present, though at much lower levels. The progesterone receptor level, the epidermal growth factor receptor level, and the age of the patients are not correlated with the estrogenic 17 beta-HSD activity or type-2 17 beta-HSD mRNA expression level.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Pubertal changes in testicular 3 beta-hydroxysteroid dehydrogenase activity in a male with classical 3 beta-hydroxysteroid dehydrogenase deficiency showing spontaneous secondary sexual maturation.

Males with classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency manifest appropriate secondary sexual maturation with an elevation in serum testosterone levels at pubertal age. To define the origin of serum testosterone, we evaluated a male patient with classical 3 beta-HSD who showed pubertal development. High values of testosterone and a ratio of delta(5) to delta(4) steroids in the spermatic vein indicated direct production of considerable amounts of testosterone and a persistent defect of 3 beta-HSD activity in the gonad. Immunohistochemical analysis showed distinct immunoreactivity in the Leydig cells of the patient. The patient was homozygous for a nonsense mutation in the type-II 3 beta-HSD gene. We propose that gonadal type-I 3 beta-HSD could be expressed by gonadotropin stimulation at pubertal age, and delta(4)-steroid precursors would convert to testosterone.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene in a patient with classic salt-wasting 3 beta-hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia.

Inherited adrenal and gonadal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is most likely caused by a mutation of the type II 3 beta-HSD gene. Cloning and sequencing of exons I-II, III, and IV and portions of the adjacent introns, amplified by polymerase chain reaction using primers specific for the type II gene, in one male pseudohermaphrodite with salt-wasting classic 3 beta-HSD deficiency congenital adrenal hyperplasia revealed the same mutation in all nine clones of exon IV consisting of a missense mutation at codon 248 [GTC(Val)-->AAC(Asn)] followed by a frameshift mutation at codon 249 [CGA (Arg)-->TA], resulting in a stop codon TAG, and normal sequences of exon I-II and III and the adjacent portions of introns. The same codon 248 and 249 mutations were found on one clone of his mother's DNA, but two other clones revealed normal sequences. These data indicate a homozygous combined missense/frameshift mutation in exon IV of the type II 3 beta-HSD gene resulting in severe salt-wasting adrenal and gonadal 3 beta-HSD deficiency in the patient.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Characterization of type 12 17beta-hydroxysteroid dehydrogenase, an isoform of type 3 17beta-hydroxysteroid dehydrogenase responsible for estradiol formation in women.

A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. Both are encoded by large genes spanning 11 exons, most of them showing identical size. Using human embryonic kidney-293 cells stably expressing 17beta-HSD12, we have found that the enzyme catalyzes selectively and efficiently the transformation of E1 into E2, thus identifying its role in estrogen formation, in contrast with 17beta-HSD3, the enzyme involved in the biosynthesis of the androgen testosterone in the testis. Using real-time PCR to quantify mRNA in a series of human tissues, the expression levels of 17beta-HSD12 as well as two other enzymes that perform the same transformation of E1 into E2, namely type 1 17beta-HSD and type 7 17beta-HSD, it was found that 17beta-HSD12 mRNA is the most highly expressed in the ovary and mammary gland. To obtain a better understanding of the structural basis of the difference in substrate specificity between 17beta-HSD3 and 17beta-HSD12, we have performed tridimensional structure modelization using the coordinates of type 1 17beta-HSD and site-directed mutagenesis. The results show the potential role of bulky amino acid F234 in 17beta-HSD12 that blocks the entrance of androstenedione. Overall, our results strongly suggest that 17beta-HSD12 is the major estrogenic 17beta-HSD responsible for the conversion of E1 to E2 in women, especially in the ovary, the predominant source of estrogens before menopause.

17-Hydroxysteroid Dehydrogenases↗
PubMed2006

Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma.

Type 2 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) is a multi-functional enzyme that possesses 3alpha-, 17beta- and 20alpha-HSD, as well as prostaglandin (PG) F synthase activities and catalyzes androgen, estrogen, progestin and PG metabolism. Type 2 3alpha-HSD was cloned from human prostate, is a member of the aldo-keto reductase (AKR) superfamily and was named AKR1C3. In androgen target tissues such as the prostate, AKR1C3 catalyzes the conversion of Delta(4)-androstene-3,17-dione to testosterone, 5alpha-dihydrotestosterone to 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), and 3alpha-diol to androsterone. Thus AKR1C3 may regulate the balance of androgens and hence trans-activation of the androgen receptor in these tissues. Tissue distribution studies indicate that AKR1C3 transcripts are highly expressed in human prostate. To measure AKR1C3 protein expression and its distribution in the prostate, we raised a monoclonal antibody specifically recognizing AKR1C3. This antibody allowed us to distinguish AKR1C3 from other AKR1C family members in human tissues. Immunoblot analysis showed that this monoclonal antibody binds to one species of protein in primary cultures of prostate epithelial cells and in LNCaP prostate cancer cells. Immunohistochemistry with this antibody on human prostate detected strong nuclear immunoreactivity in normal stromal and smooth muscle cells, perineurial cells, urothelial (transitional) cells, and endothelial cells. Normal prostate epithelial cells were only faintly immunoreactive or negative. Positive immunoreactivity was demonstrated in primary prostatic adenocarcinoma in 9 of 11 cases. Variable increases in immunoreactivity for AKR1C3 was also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy and urothelial (transitional) cell metaplasia. We conclude that elevated expression of AKR1C3 is highly associated with prostate carcinoma. Although the biological significance of elevated AKR1C3 in prostatic carcinoma is uncertain, AKR1C3 may be responsible for the trophic effects of androgens and/or PGs on prostatic epithelial cells.

3-Hydroxysteroid Dehydrogenases↗
PubMed1977

Endocrine regulation of sex-dependent hydroxysteroid dehydrogenase activities in rat kidney: NADP-dependent microsomal 3alpha- and 20beta-hydroxysteroid dehydrogenase.

The NADP-dependent microsomal kidney enzymes, 3alpha- and 20beta-hydroxysteroid dehydrogenase (HSDH), which exhibit considerable sex differences in their activities (male:female activity ratios, 16:1 and 30:1 respectively), were investigated after interference with the pituitary-gonad and pituitary-adrenal systems. Prepubertal gonadectomy as well as hypophysectomy of mature male rats led to a decline in HSDH activity to almost that found in the normal female rat, whereas activities in female rats were unaffected. Testosterone induced typical male 3alpha-HSDH activity in both gonadectomized and hypophysectomized rats of either sex. Administration of 5alpha-dihydrotestosterone (5alpha-DHT) or 5alpha-androstane-3alpha, 17beta-diol to hypophysectomized male rats was equally effective in restoring full 3alpha- and 20beta-HSDH activities whereas 5alpha-androstane-3beta, 17beta-diol was less effective and dehydroepiandrosterone was ineffective. Simultaneous administration of cyproterone acetate did not block the inductive action of 5alpha-DHT. Administration of chorionic gonadotrophin, pregnant mare serum gonadotrophin or a combination of luteinizing hormone and follicle-stimulating hormone to hypophysectomized male rats all led to parallel increases in the weight of the seminal vesicles and in both renal enzyme activities; administration of growth hormone, prolactin or thyroid-stimulating hormone was ineffective. Adrenalectomy of gonadectomized, but not of hypophysectomized male rats, caused a further drop in activity to the normal female level. Adrenalectomy of otherwise intact rats did not affect either enzyme activity. The hypophysis was involved in the regulation of the two NADP-dependent renal HSDH activities through its gonadotrophic function in male rats; adrenal secretions were of little physiological significance.

Adrenalectomy↗
PubMed1992

Pig testicular 20 beta-hydroxysteroid dehydrogenase exhibits carbonyl reductase-like structure and activity. cDNA cloning of pig testicular 20 beta-hydroxysteroid dehydrogenase.

cDNA inserts encoding 20 beta-hydroxysteroid dehydrogenase (EC 1.1.1.53) were, for the first time, isolated and cloned from a pig testis cDNA library using synthetic oligonucleotides deduced from the partially determined amino acid sequences. The cDNA contains an open reading frame predicted to encode 289 amino acid residues. Surprisingly, it has 85% amino acid homology to human carbonyl reductase. The purified enzyme exhibited carbonyl reductase activity. Adenine-rich sequence was located in the 3'-untranslated nine-rich sequence was located in the 3'-untranslated region, which may mean that the gene originates by retroposition. RNA transcripts of 1.3, 3, and 6 kilobases were detected in poly(A)+ RNA extracted from pig testis by Northern blot hybridization. The steady-state level of the RNA species increased to a maximum in testes from 10-day-old pigs, but rapidly declined thereafter to the same levels found in testes of mature animals.

Alcohol Oxidoreductases↗
PubMed1994

Structure, regulation and role of 3 beta-hydroxysteroid dehydrogenase, 17 beta-hydroxysteroid dehydrogenase and aromatase enzymes in the formation of sex steroids in classical and peripheral intracrine tissues.

In addition to the classical steroidogenic tissues, namely the ovaries, testes, adrenals and placenta, a large series of human peripheral tissues possess all the enzymatic systems required for the formation of active androgens and oestrogens from a relatively large supply of precursor steroids provided by the adrenals. This chapter describes the structure, function, tissue-specific expression and regulation of the 3 beta-HSD and 17 beta-HSD gene families as well as some information about the aromatase gene. While, so far, most therapeutic approaches have been aimed and limited at controlling steroid formation by the classical steroidogenic tissues, it is clear that major efforts should now be turned towards intracrinology in order to understand better the physiological mechanisms controlling local steroid formation in peripheral target tissues and thus be in a position to develop novel therapeutic approaches that take into account the high proportion of steroids that are made locally and are responsible for the growth and function of normal as well as cancerous tissue.

17-Hydroxysteroid Dehydrogenases↗
PubMed1995

[Cloning of genes coding for 3-alpha-hydroxysteroid dehydrogenase and for (3-17)-beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni].

A genomic library of Pseudomonas testosteroi total DNA constructed from SauIIIA digests ligated to a lambda gt11 vector was probed with different polyclonal antibodies raised against purified 3 alpha-HSD and (3 beta-17 beta)-HSD. Two different clones reacting with one antibody were selected. The clone reacting with (3-17)beta-HSD antibody contained a 2,661-base pair insert and was found to contained an open reading frame of 765 base pair that corresponds to a protein of 254 amino-acid residues. A 1,492-base pair was inserte in pBR 322 plasmid vector; the recombinant bacterie over expressed the (3-17)beta-HSD gene. The clone reacting with 3 alpha-HSD antibody contained a 1746 base pair insert which contained an open reading frame of 696 base pairs that corresponds to a protein of 231 amino-acid residues. A search for homologous proteins was performed. Distant similarities were found between (3-17)beta-HSD and members of the short-chain alcool dehydrogenase (SCAD) family but no similarity was observed between 3 alpha-HSD and proteins of this family.

3-Hydroxysteroid Dehydrogenases↗