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Biomedical subjects

C Martel

Publications and source records attributed to C Martel.

At least 37 records · Page 2Linked to original sources
PubMed1997

Long-term inhibitory effects of a novel anti-estrogen on the growth of ZR-75-1 and MCF-7 human breast cancer tumors in nude mice.

The effects of the novel anti-estrogen EM-343 on the growth of 2 hormone-responsive human breast cancer tumors have been examined in athymic nude mice. At the low daily dose of 5 microg, EM-343 administered subcutaneously for 6 months completely blocked the stimulatory effect of endogenous estrogens on the growth of ZR-75-1 and MCF-7 tumors implanted in nude mice. In addition, uterine weight decreased by 60% while ovarian weight increased by 37%. Estrogen receptor (ER) levels measured by [3H]-labeled estrogen binding were markedly reduced (by 96%, 96% and 92%) in ZR-75-1 and MCF-7 tumors, and in the mouse uterus, respectively. Accompanying the decrease in ER, progesterone receptor levels were reduced by 79%, 87% and 76%, respectively, in the above-mentioned tissues following EM-343 treatment. Our data show the pure anti-estrogenic properties of EM-343 and its high potency as an inhibitor of growth of human ZR-75-1 and MCF-7 breast tumors in nude mice.

Animals↗
PubMed1997

Comparative effects of 28-day treatment with the new anti-estrogen EM-800 and tamoxifen on estrogen-sensitive parameters in intact mice.

Following 28 days of oral administration, in intact mice, the novel non-steroidal anti-estrogen EM-800 was at least 30-fold more potent than tamoxifen in inhibiting uterine weight. Moreover, the maximal inhibitory effect achieved with tamoxifen on uterine weight was only 40% that with EM-800. The pure anti-estrogenic activity of EM-800 on the hypothalamo-pituitary-gonadal axis is illustrated by the increase in ovarian weight, while tamoxifen, due to its estrogenic activity, decreased ovarian weight. EM-800 is 10- to 30-fold more potent than tamoxifen in inhibiting uterine and vaginal estrogen receptors. Since 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is the key enzyme in estradiol formation, the potent inhibitory effect of EM-800 on uterine 17beta-HSD could play an additional role by decreasing the availability of estradiol in the uterine tissue, while tamoxifen, on the contrary, stimulates activity of the enzyme. The atrophic changes in both the endometrial and myometrial layers achieved with EM-800 almost reached those observed 28 days after ovariectomy. EM-800 also resulted in a marked decrease in the number of ovarian developing follicles and corpora lutea, while the number of atretic follicles was increased. Tamoxifen treatment, on the other hand, produced an increase in both the number and crowding of the endometrial glands and a mild atrophy of the myometrial layer. Tamoxifen caused atrophic changes of the vaginal epithelium, especially at the highest doses, though the atrophy was much less pronounced than that following EM-800 treatment or ovariectomy. In addition to being at least 30-fold more potent than tamoxifen in inhibiting uterine weight, the novel anti-estrogen causes atrophy of the endometrium, stimulates the hypothalamo-pituitary-gonadal axis and inhibits uterine 17beta-HSD activity, while tamoxifen exerts opposite and estrogen-like effects on these parameters.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity.

OBJECTIVES: Because the large increase in luteinizing hormone secretion induced by flutamide in the intact rat is not found in men, we have used castrated rats and mice supplemented with androstenedione (4-dione) instead of intact animals to measure the activity of the pure antiandrogens flutamide and Casodex. METHODS: We first compared the effect of different schedules of administration of various doses of the two antiandrogens on prostate and seminal vesicle weights in the castrated rat and mice models. RESULTS: For both flutamide and Casodex, no consistent difference was found between the effects of once daily and thrice daily oral dosing in the rat. It was observed, however, that flutamide, especially at the high and therapeutically more effective doses, is about three times more potent than Casodex under both schedules of dosing. When flutamide was administered subcutaneously three times a day, twice a day, once a day, or once every second day in rats and mice, no difference was observed in the degree of inhibition achieved on prostate and seminal vesicle weights. CONCLUSIONS: The present data show that Casodex is about three times less potent than flutamide on the well-recognized parameters of androgen responsiveness in the rat, namely prostate and seminal vesicle weights. Another finding is that once daily dosing with flutamide exhibits an effectiveness comparable to thrice daily dosing; such data may have potential significance in facilitating compliance by administration of flutamide once daily instead of the current thrice daily schedule in men. Moreover, these data, if obtained in a reliable in vivo model, should be helpful in determining the choice of an appropriate dose of Casodex for the treatment of prostate cancer.

Androgen Antagonists↗
PubMed1997

Effects of tedisamil, atenolol and their combination on heart and rate-dependent QT interval in healthy volunteers.

AIMS: Tedisamil is a new blocker of K+ currents in cardiac tissues, exerts bradycardic effects and has shown clinical efficacy in angina pectoris. Theoretically, when coadministered with a beta-adrenoceptor blocker the tedisamil combination could induce dangerous bradycardia and QT interval prolongation. Therefore, the aim of this study was to evaluate the effects of tedisamil and atenolol alone and in combination, on heart rate and QT interval duration at rest and during exercise tests. METHODS: The effects of tedisamil (100 mg twice daily) and atenolol (50 mg twice daily) on heart rate and QT interval duration were analysed in a three-period crossover study in healthy male volunteers. RESULTS: This study showed that tedisamil exerted a significant (P<0.05) bradycardic action at rest (-10 beats min(-1); 95% CI: -6 to -15 beats min(-1)) similar to atenolol (-14 beats min(-1); -11 to -17) and drug combination (-9 beats min(-1); -6 to -12). During exercise, at the highest comparable workload, heart rate did not decrease significantly with tedisamil but decreased significantly with atenolol (-42 beats min(-1); -37 to -47) and combination (-47 beats min(-1); -41 to 52). Atenolol did not modify QT interval duration. Tedisamil alone and in combination with atenolol increased QT interval duration by 12% (95% CI: 7 to 17%) and 12% (8 to 16) respectively at RR=1000 ms, but not at RR<700 ms (combination). Tedisamil alone and in combination induced a reverse rate-dependent QT interval prolongation. CONCLUSIONS: These results indicate that the combination of tedisamil and atenolol is not associated with excessive bradycardia or excessive QT interval prolongation in healthy subjects.

Adrenergic beta-Antagonists↗
PubMed1997

Inactivation of retinoblastoma family proteins by SV40 T antigen results in creation of a hepatocyte growth factor/scatter factor autocrine loop associated with an epithelial-fibroblastoid conversion and invasiveness.

SV40 T antigen (LT) is an oncoprotein that inactivates nuclear regulators such as retinoblastoma (RB) family proteins and p53. We recently reported that in Madin-Darby canine kidney (MDCK) epithelial cells the binding of LT to RB family proteins results in a massive apoptosis and a concomitant down-regulation of c-myc. Here, we show that LT causes loss of epithelial differentiation and induces invasiveness. MDCK cells expressing wild-type LT, but not mutants unable to bind RB, exhibit a fibroblast-like morphology, show a strong down-regulation of the vHNF1 transcription factor and acquire invasive properties. The stable retransformation of MDCK(LT) with a RB and/or c-myc-expressing vector restores the expression of epithelial characteristics. Our data therefore suggest an important role for RB and c-myc in modulating the epithelial phenotype both during normal tissue development and in invasive processes. In addition, when grown in collagen gels, the MDCK(LT) cells form branching tubules, and their conditioned media produce the scattering of monolayer cultured MDCK cells. These last properties are reminiscent of those induced by hepatocyte growth factor/scatter factor (HGF/SF). Moreover, the HGF/SF protein was detected by Western blotting in the MDCK(LT)-conditioned medium. The production of HGF/SF is specifically induced by LT-RB inactivation, because Ras transformation of MDCK cells fails to induce the production of this factor. These results demonstrate that inactivation of RB family proteins in these cells is at the origin of a HGF/SF autocrine loop.

Animals↗
PubMed1996

Inactivation of retinoblastoma gene product RB or an RB-related protein by SV40 T antigen in MDCK epithelial cells results in massive apoptosis.

SV40 T antigen (LT) transformation of renal MDCK epithelial cells resulted in massive apoptosis in the presence of serum. Cell death was dependent on the ability of LT to bind RB or a related protein, since MDCK cells expressing LT mutants unable to bind RB did not die. Apoptosis could be rescued by treatment of cells with EGF and TPA, a property linked to their ability to promote cell growth. Our results indicate an inverse correlation between proliferation and apoptosis. Thus LT transformation induced survival-factor dependence in epithelial cells, in contrast to its effect in fibroblasts. RB inactivation also resulted in a strong down-regulation of c-myc and c-fos, which were previously found to be highly and constitutively expressed in epithelial cells. RB gene transfer in MDCK(LT) cells restored cell viability and high c-myc expression. C-myc gene transfer in these cells also resulted in a significant survival effect. These results suggest that RB anti-cell death activity is at least partly mediated by up-regulation of c-myc. Overexpression of Bcl2 also protected cells against apoptosis. The role of RB and c-myc in cell survival is discussed and related to maintenance of the differentiation state rather than to their properties in cell cycle progression.

Journal Article↗
PubMed1995

Characterization of neutrophil NADPH oxidase activity reconstituted in a cell-free assay using specific monoclonal antibodies raised against cytochrome b558.

The immunochemical characterization of NADPH oxidase activity of cytochrome b558 purified from human neutrophils was determined after reconstitution in a cell-free assay using the native hemoprotein and recombinant purified cytosolic activating factors. The oxidase activity showed a strict dependence on the heme content at each step of the hemoprotein purification process. The immunochemical properties of the reconstituted oxidase made use of monoclonal antibodies raised against membrane-bound and octyl-glucoside-extracted cytochrome b. From nine specific monoclonal antibodies reacting with gp91-phox cytochrome b558, two were selected, both of which were found to bind to the beta subunit of cytochrome b558 and to inhibit superoxide formation in the oxidase reconstituted cell-free assay. The extent of inhibition was dependent on the phospholipid environment. Neutrophil membrane extracts from X-linked chronic granulomatous disease patients did not produce O2- in the reconstituted system and did not bind to the antibodies.

Animals↗
PubMed1995

Specific c-myc and max regulation in epithelial cells.

We have investigated c-myc, max and c-fos mRNA and protein expression in proliferating, quiescent and stimulated immortalized, SV40 T antigen (LT) transformed and tumor-derived epithelial cells as well in human primary keratinocytes and have compared them to their expression in fibroblasts. In proliferating immortalized and tumor-derived epithelial cells, the levels of c-myc, max and c-fos expression were comparable and much higher than in transformed fibroblasts. c-myc and c-fos mRNA and protein levels remained high even during quiescence, when cells stopped dividing. In contrast, whereas max mRNA was constitutively expressed, max protein levels decreased in both fibroblasts and epithelial cells at high cell density. Changing the medium to serum-free medium of confluent epithelial cells induced a complete proliferative response which started with a transient increase in c-fos and c-myc mRNA, followed by the expression of max. Addition of serum to the medium did not induce additional effects. In fibroblasts, similar treatment induced the arrest of c-myc expression and growth, but max expression was also induced in these cells by serum. Our results therefore show that max expression is growth regulated in both immortalized and transformed epithelial as well as fibroblast cells. In contrast, in epithelial cells, c-myc displayed two contrasting behaviors.

Animals↗
PubMed1994

Widespread tissue distribution of steroid sulfatase, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD), 17 beta-HSD 5 alpha-reductase and aromatase activities in the rhesus monkey.

Dehydroepiandrosterone-sulfate (DHEA-S), the main secretory product of the human adrenal, requires the presence of steroid sulfatase, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), 5 alpha-reductase, and aromatase to form the active androgen dihydrotestosterone (DHT) and the estrogens 17 beta-estradiol (E2) and 5-androst-ene-3 beta,17 beta-diol (delta 5-diol) in peripheral target tissues. Because humans, along with non-human primates are unique in having adrenals that secrete large amounts of DHEA-S, the present study investigated the tissue distribution of the enzymatic activity of the above-mentioned steroidogenic enzymes required for the formation of active sex steroids in the male and female rhesus monkey. Estrone and DHEA sulfatase activities were measured in all 25 tissues examined, and with the exception of the salivary glands, estrogenic and androgenic 17 beta-HSDs were present in all the tissues examined. The adrenal, small and large intestine, kidney, liver, lung, fat, testis, prostate, seminal vesicle, ovary, myometrium, and endometrium all possess the above-mentioned enzymatic activities, thus suggesting that these tissues could possibly form the biologically active steroids E2 and DHT from the adrenal precursor DHEA-S. On the other hand, the oviduct, cervix, mammary gland, heart, and skeletal muscle possess all the enzymatic activities required to synthesize E2 from DHEA-S. The present study describes the widespread tissue distribution of steroid sulfatase, 3 beta-HSD, 17 beta-HSD, 5 alpha-reductase, and aromatase activities in rhesus monkey peripheral tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Rapid modulation of ovarian 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase gene expression by prolactin and human chorionic gonadotropin in the hypophysectomized rat.

In order to better understand the role of prolactin (PRL) and luteinizing hormone (LH) on progesterone biosynthesis in the ovary, we have investigated the time course (1-9 days) of the effect of PRL and human chorionic gonadotropin (hCG) on ovarian 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) expression in the hypophysectomized rat. As evaluated by quantitative in situ hybridization using a 35S labelled type I 3 beta-HSD cDNA probe, the administration of hCG for 2, 3 and 9 days induced increases of 63%, 145% and 146% above control, respectively, in 3 beta-HSD mRNA levels in ovarian interstitial cells. The absence of apparent effect of the gonadotropin in other ovarian cell types could explain the small modulation of ovarian 3 beta-HSD protein content and enzymatic activity observed in total ovarian tissue. On the other hand, treatment with PRL caused a rapid decrease in 3 beta-HSD mRNA levels in corpus luteum by 23%, 63%, 76% and 78% (P < 0.01) following 1, 2, 5 and 9 days of treatment, respectively. The short-term inhibitory effect of PRL was also observed on ovarian immunoreactive 3 beta-HSD protein, as measured by Western blot analysis, and on 3 beta-HSD activity measured by the conversion of [14C]dehydroepiandrosterone into [14C]androstenedione.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Opposite effects of prolactin and corticosterone on the expression and activity of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase in rat skin.

In rat skin, type IV is the major 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzyme expressed. Although types I and II 3 beta-HSD mRNAs are also present in the skin, their level of expression is about two orders of magnitude lower than that of type IV. In this study, we have investigated the control of type IV 3 beta-HSD mRNA levels as well as 3 beta-HSD enzymatic activity in hypophysectomized adult rats of both sexes. Skin 3 beta-HSD activity was measured by the conversion of [14C]-dehydroepiandrosterone into [14C]-androstenedione, whereas ribonuclease protection assay using a specific type IV cRNA probe was used to assess mRNA levels. Intact male and female rats show a similar level of skin 3 beta-HSD activity, although hypophysectomy caused opposite effects, a decrease being observed in males while an increase was observed in hypophysectomized female animals. We next studied the effects of hyperprolactinemia, corticosterone and 1-thyroxine in hypophysectomized animals. L-thyroxine was found to stimulate 3 beta-HSD expression and activity in male rats whereas no significant effect was observed on the already elevated levels in hypophysectomized female rats. Corticosterone caused an inhibition of type IV 3 beta-HSD mRNA levels and activity in both male and female animals. Hyperprolactinemia achieved by pituitary implants inserted under the kidney capsule stimulated the expression of type IV mRNA as well as 3 beta-HSD enzymatic activity in hypophysectomized male and female animals. The present data demonstrate the multihormonal regulation of 3 beta-HSD/isomerase expression and activity in the rat skin.

Animals↗
PubMed1994

Effect of estrone on the growth of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in the rat: a model of postmenopausal breast cancer.

Estradiol (E2) is well known as stimulator of the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. The effect of estrone (E1), however, has not been described in this model of human breast cancer. As E1 is the predominant estrogen precursor in postmenopausal women, we have investigated the effect of this steroid and, simultaneously, the potential role of the enzyme required for interconversion of the weak estrogen E1 into the potent estrogen E2, namely 17 beta-hydroxysteroid dehydrogenase, in the growth of DMBA-induced mammary carcinoma in the rat. Treatment for 20 days of ovariectomized animals bearing DMBA-induced mammary tumors with twice daily doses of 0.375, 0.75, 1.5, and 3.0 micrograms E1 increased total tumor area by 48%, 101%, 116%, and 129%, respectively. Treatment with the highest dose of E1 increased progesterone receptor levels by 20.4- and 2.3-fold in the DMBA-induced tumors and uterus, respectively. After treatment with E1, the concentration of this steroid was similar in the serum and tumor tissue, whereas concentrations of E2 were approximately 3-fold higher in the tumor tissue compared to serum. Treatment with a 1.0-microgram dose of E1 caused a 60% increase in tumoral 17 beta-hydroxysteroid dehydrogenase activity in ovariectomized animals, thus favoring E2 formation from E1 in tumors. In addition, treatment with the 1.0-microgram dose of E1 or 0.1 microgram E2 gave similar stimulatory effects on tumor growth and uterine weight in ovariectomized animals; the values were comparable to those found in intact animals. The present data indicate that ovariectomized rats bearing DMBA-induced mammary tumors and treated with E1 can be a useful model of postmenopausal breast cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed1993

The O2- generating oxidase of B lymphocytes: Epstein-Barr virus-immortalized B lymphocytes as a tool for the identification of defective components of the oxidase in chronic granulomatous disease.

The O2- generating NADPH oxidase of human Epstein-Barr virus immortalized B lymphocytes (EBV-B lymphocytes) and the NADPH oxidase of human neutrophils were compared. The capacity of the oxidase of EBV-B lymphocytes to generate O2- is 100-fold less than that of neutrophils. Like the oxidase of neutrophils, the oxidase of EBV-B lymphocytes is decreased or abolished in chronic granulomatous disease (CGD). Activation of neutrophil oxidase in an heterologous cell-free system, using human neutrophil membranes and EBV-B lymphocyte cytosol from healthy and CGD patients, combined with immunoblotting investigations of the cytosolic activating factors p47 and p67 involved in O2- production, suggests that neutrophils and EBV-B lymphocytes possess similar complements of cytosolic factors p47 and p67. Cytochrome b -245, the major membrane redox component of the O2- generating oxidase, is only slightly expressed in the membrane of EBV-B lymphocytes. A sensitive and specific immunocytochemical method for detection of the two subunits of cytochrome b -245 is described; it shows that both subunits are virtually absent in EBV-B lymphocytes from CGD patients deficient in the large subunit.

Animals↗
PubMed1993

Blockade of androstenedione-induced stimulation of androgen-sensitive parameters in the rat prostate by combination of Flutamide and 4-MA.

In order to mimic the human situation in which adrenal steroid precursors are converted to the active androgen dihydrotestosterone (DHT) in prostatic tissue, we have used castrated rats supplemented with the precursor steroid androstenedione (delta 4-dione) released from Silastic implants. While it is well known that the action of DHT can be partially neutralized by antiandrogens which compete for binding to the androgen receptor, we have used 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), an inhibitor of 5 alpha-reductase, the enzyme which converts testosterone into DHT, in order to decrease intraprostatic DHT levels and thus facilitate the action of the antiandrogen. Animals were treated for 7 days with Flutamide (FLU, 2 mg) or 4-MA (4 mg) injected subcutaneously, twice daily, alone or in combination. 4-MA administered alone caused a 54% inhibition of delta 4-dione-stimulated ventral prostate weight while FLU exerted a 74% inhibitory effect and 4-MA+FLU further improved inhibition to 81%. We then measured, by in situ hybridization, the levels of prostatic mRNAs encoding the C1 and C3 components of the prostatic binding protein (PBP) which are highly specific and sensitive markers of androgen action. PBP-C3 mRNA levels fell by 95% following castration while treatment with delta 4-dione completely reversed the effect of castration. Administration of FLU or 4-MA independently caused 33% and 10% decreases, respectively, of PBP-C3 mRNA levels stimulated by delta 4-dione while the combination of both compounds further inhibited PBP-C3 mRNA levels to reach a 55% inhibition. Similar effects were observed on PBP-C1 mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗
PubMed1992

Novel compounds inhibit estrogen formation and action.

Estrogens are well known to play a predominant role in human breast cancer. The current endocrine therapy of breast cancer consists in administering an antiestrogen which blocks the action of estrogens at the receptor level. However, the currently available antiestrogens possess mixed estrogenic and antiestrogenic activity, thus limiting their potential therapeutic efficacy. The present data show that a series of new estrogen derivatives demonstrate not only pure antiestrogenic activity in the sensitive in vivo mouse uterus assay, but simultaneously exert potent inhibitory effects on 17 beta-hydroxysteroid dehydrogenase activity, the enzyme responsible for the formation of 17 beta-estradiol from estrone, the last step in estrogen formation. Such compounds having a dual site of inhibitory action, namely on estrogen formation and on the estrogen receptor, could well lead to an improved endocrine therapy of breast and other estrogen-sensitive cancers as well as other nonmalignant estrogen-sensitive diseases.

17-Hydroxysteroid Dehydrogenases↗
PubMed1992

Distribution of 17 beta-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues.

The interconversion of estrone (E1) and 17 beta-estradiol (E2), androstenedione (4-ene-dione) and testosterone (T), as well as dehydroepiandrosterone and androst-5-ene-3 beta,17 beta-diol is catalyzed by 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD). The enzyme 17 beta-HSD thus plays an essential role in the formation of all active androgens and estrogens in gonadal as well as extragonadal tissues. The present study investigates the tissue distribution of 17 beta-HSD activity in the male and female rat as well as in some human tissues and the distribution of 17 beta-HSD mRNA in some human tissues. Enzymatic activity was measured using 14C-labeled E1, E2, 4-ene-dione and T as substrates. Such enzymatic activity was demonstrated in all 17 rat tissues examined for both androgenic and estrogenic substrates. While the liver had the highest level of 17 beta-HSD activity, low but significant levels of E2 as well as T formation were found in rat brain, heart, pancreas and thymus. The oxidative pathway (E2----E1, T----4-ene-dione) was favored over the reverse reaction in almost all rat tissues while in the human, almost equal rates were found in most of the 15 tissues examined. The widespread distribution of 17 beta-HSD in rat and human tissues clearly indicates the importance of this enzyme in peripheral sex steroid formation or intracrinology.

17-Hydroxysteroid Dehydrogenases↗
PubMed1992

Regulation of 3-ketosteroid reductase messenger ribonucleic acid levels and 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase activity in rat liver by sex steroids and pituitary hormones.

We have recently characterized three types of complementary DNA clones encoding predicted isoenzymes of the rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) family. Transient expression in nonsteroidogenic cells reveals that the type III isoenzyme specific for male liver does not display oxidative activity for classical substrates of 3 beta-HSD, in contrast to the two other 3 beta-HSD isoenzymes, thus showing exclusively 3-ketosteroid reductase (3-KSR) activity. In order to better understand the sex-specific control of 3 beta-HSD activity and type III 3-KSR gene expression in rat liver, we have studied in adult animals of both sexes the effect of sex steroids and hypophysectomy, pituitary implants, PRL, and GH on type III 3-KSR messenger RNA (mRNA) levels and 3 beta-HSD/delta 5-delta 4 isomerase activity as measured by the conversion of [14C]dehydroepiandrosterone into [14C] delta 4-androstenedione. Ribonuclease protection assay using types I-, II-, and III-specific complementary RNA probes reveals that type III transcripts are the only species detectable in liver RNA extracted from intact males, whereas no hybridization signal was detectable with any of the three probes in intact female liver RNA. In males, 15 days after castration, liver type III 3-KSR mRNA levels decreased by 80% compared to intact controls, whereas 3 beta-HSD activity was reduced by 48%. Administration of dihydrotestosterone (DHT) increased by 8.25-fold type III 3-KSR mRNA concentration and completely reversed the inhibitory effect of orchiectomy on 3 beta-HSD activity. In ovariectomized animals, treatment with DHT markedly increased type III 3-KSR mRNA accumulation and 3 beta-HSD activity, thus leading to values similar to those measured in intact males. Simultaneous treatment with 17 beta-estradiol almost completely abolished the stimulatory effect of DHT in female rats, whereas no significant effect was seen in males. Twenty-four days after hypophysectomy, type III 3-KSR mRNA levels were decreased by 50-55% in males, whereas in females these transcripts markedly increased from undetectable to 28-36% of the value measured in intact male rats. Treatment with DHT or 17 beta-estradiol for a period of 9 days starting 15 days after hypophysectomy had no effect in male and female rats. On the other hand, treatment with ovine PRL (1 mg, twice daily) had no effect in males but completely blocked the elevation of type III 3-KSR mRNA levels and 3 beta-HSD activity observed after hypophysectomy in females.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxysteroid Dehydrogenases↗