Disease relevance of HSD3B

• The finding of a normal type I 3 beta-HSD gene explains the elevated delta 5-steroids and mild virilization of affected girls at birth [1].
• 3 beta-HSD deficiency, transmitted in an autosomic recessive disorder, is characterized by varying degrees of salt wasting; in genetic males, fetal testicular 3 beta-HSD deficiency causes an undervirilized male genitalia (male pseudohermaphroditism); females exhibit either normal sexual differentiation or mild virilization [1].

High impact information on HSD3B

• The 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta HSD) enzyme catalyzes the oxidation and isomerization of delta 5-3 beta-hydroxysteroid precursors into delta 4-ketosteroids, thus leading to the formation of all classes of steroid hormones [2].
• The present data show for the first time that adrenals and gonads express a type of 3 beta HSD isoenzyme that is distinct from the type expressed in the placenta.(ABSTRACT TRUNCATED AT 400 WORDS)[2]
• Moreover, incubation in the presence of NADH of homogenates from cells transfected with type I or type II 3 beta HSD indicates that dihydrotestosterone is converted into 5 alpha-androstane-3 beta, 17 beta-diol, with Km values of 0.26 and 2.7 microM, respectively [2].
• To characterize and compare the kinetic properties of the two isoenzymes, plasmids derived from pCMV and containing type I or type II 3 beta HSD full-length cDNA inserts were transiently expressed in HeLa human cervical carcinoma cells [2].
• Such intermembrane fusion sites would facilitate the access of cholesterol to the inner membrane in which cholesterol side-chain cleavage cytochrome P-450 is located as well as the rapid transformation of its reaction product (i.e. pregnenolone) to progesterone by 3 beta HSD/I [3].

Biological context of HSD3B

• We have used our recently characterized human 3 beta-hydroxy-5-ene steroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) cDNA as probe to isolate cDNAs encoding bovine 3 beta-HSD from a bovine ovary lambda gtll cDNA library [4].
• The deduced amino acid sequence of bovine 3 beta-HSD displays 79% homology with human 3 beta-HSD while the nucleotide sequence of the coding region shares 82% interspecies similarity [4].
• The results suggest that mitochondrial 3 beta HSD is an integral inner membrane protein, that the active site faces the matrix space and is influenced by coenzyme availability, and that a regulatory site(s) faces the intermembrane space [5].
• The levels of 3 beta HSD were extremely low in placental tissues, but were higher in the fetal adrenals, where they were found to be slightly elevated in early and late gestation compared to those in midgestational stages [6].
• 3 beta HSD mRNA levels in granulosa cells were 4.2-fold higher in early vs. late follicular phase (P < 0.01) [7].

Anatomical context of HSD3B

• Examination of submitochondrial preparations revealed that 3 beta HSD/I was associated with both the inner membrane and a particulate fraction that sediments in a density gradient between inner and outer membranes [3].
• In these experiments we examined the membrane topologies of 3 beta HSD in rat and calf adrenal microsomes and mitochondria by comparing access to the active sites of coenzyme and the inhibitor mersalyl, a nonpenetrant organic mercurial anion [5].
• After 72 h of culture, the signal for P450scc and 3 beta HSD mRNA in granulosa cells exposed to LH was higher than the signal detected in cultures without LH (P < 0.01) [7].
• Immunocytochemical examination of the levels of P45017 alpha and 3 beta HSD in the fetal adrenal glands correlated with the results of Western and Northern analyses [6].
• However, because the different stabilities of 3 beta HSD and hydroxylase proteins and/or mRNAs may play a critical role in determining the zone-specific steroids secreted from the adrenal cortex, other cAMP-dependent or independent regulatory mechanisms may also be important in regulating the expression of adrenal 3 beta HSD [8].

Associations of HSD3B with chemical compounds

• Our objective was to determine whether changes in progesterone production by the preovulatory follicle are effected via changes in mRNA levels for the steroidogenic enzymes cholesterol side-chain cleavage cytochrome P450 (P450scc) and 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta HSD) [7].
• The content of 3 beta-HSD protein was measured by immunoblot analysis using an antiserum developed in rabbits against human 3 beta-HSD, whereas 3 beta-HSD activity was measured using [3H]pregnenolone, [3H] dehydroepiandrosterone, and [3H]androst-5-ene-3 beta,17 beta-diol as substrates [9].
• In contrast, mitochondrial 3 beta HSD used matrix space NAD+, was inhibited by reduction of intramitochondrial NAD(P)+, and was insensitive to mersalyl [5].
• Mitochondrial 3 beta HSD activity may be enhanced by oxidation of intermembrane space NADH via an active rotenone- and antimycin-a-insensitive NADH oxidase [5].
• 3 beta-HSD was not induced by cyclic AMP or TPA alone, but was induced by the combination of the two agents [10].

Other interactions of HSD3B

• This suggested that the lack of reactivity of FDO26G to 3 beta-HSD in extravillous trophoblast might be due to phosphorylation at serine 359 [11].
• Levels of P450scc and 3 beta-HSD mRNA were determined in extracts of total luteal RNA by ribonuclease (RNase) protection assay [12].
• After 18 h of culture, fibronectin was observed to be associated with some cells showing histochemical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity [13].
• These results described the expression of the 3 beta-HSD and the activity of this metabolic enzyme in bovine oocytes and preimplantation embryos, suggesting that steroids may act as autocrine effectors on preimplantation embryo development [14].
• A second objective was to determine if OT regulates steroidogenesis by effects on the levels of mRNA for the steroidogenic enzymes involved in progesterone synthesis, cytochrome P450 side-chain cleavage (P450scc) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), or in estradiol production, cytochrome P450 aromatase (P450arom) [15].

Analytical, diagnostic and therapeutic context of HSD3B

• Clinical observations in patients with 3 beta HSD deficiency as well as our recent data obtained by Southern blot analysis using a human placental 3 beta HSD cDNA (type I) as probe suggested the existence of multiple related 3 beta HSD isoenzymes [2].
• Expression of a male-specific (42 kDa) isoform of hepatic 3 beta HSD is dramatically suppressed in all transgenic mouse lines, as detected on Western immunoblots, without affecting a 47-kDa isoform expressed in livers of both male and female mice [16].
• After granulosa cells had been cultured for 24 h in control or LH-containing medium, P450scc and 3 beta HSD mRNA had declined dramatically compared to mRNA levels at the time of cell isolation during the early follicular phase (P < 0.01) [7].
• Follicular and luteal morphology and steroidogenic function were investigated by immunohistochemistry for cytochrome P450 17 alpha-hydroxylase (P450c17) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) during the estrous cycle in pigs, sheep, and cows [17].
• Under all circumstances levels of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), as assessed by Northern blotting or by conversion of 25-hydroxycholesterol, were very low [10].

References