MECHANISM OF THE STIMULATORY EFFECT OF CLOMID® ON AROMATIZATION OF STEROIDS BY HUMAN PLACENTA IN VITRO

1966 ◽  
Vol 51 (4) ◽  
pp. 591-598 ◽  
Author(s):  
Dwain D. Hagerman ◽  
Olive W. Smith ◽  
Caroline F. Day
Keyword(s):  
Human Placenta ◽  
Ovarian Tissue ◽  
Effective Concentration ◽  
Noncompetitive Inhibition ◽  
Significant Acceleration ◽  
Aromatization Reaction ◽  
Major Route ◽  
Minimal Effective Concentration

ABSTRACT The in vitro rate of conversion of testosterone to oestrone and oestradiol by a preparation of human placental microsomes was increased by the addition of Clomid®*. The effect was a function of the amount of Clomid added, the maximum observed being 1.6 times that in control vessels containing no Clomid. Of the cis-trans isomers of Clomid, the form designated as isomer A was three times as effective as isomer B in accelerating aromatization. The minimal effective concentration of the mixed isomers in the incubation mixture was 0.2 mm. The mechanism of this effect was shown to be a noncompetitive inhibition of the NADPH:Cytochrome c oxidoreductase system, thereby interfering with a major route of NADPH disposition in the microsomes and increasing the availability of NADPH for the aromatization reaction. The findings suggest a possible mechanism for a direct stimulatory influence of Clomid upon the ovarian biosynthesis of oestrogens in vivo, although the concentration of the drug required for significant acceleration of placental aromatization in vitro was considerably greater than its probable concentration in ovarian tissue following Clomid administration to women.

Incorporation of C14-amino acids into protein of isolated diaphragms: effect of epinephrine and norepinephrine

1960 ◽  
Vol 198 (1) ◽  
pp. 54-56 ◽  
Author(s):  
Ira G. Wool
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Glucose Concentration ◽  
Muscle Protein ◽  
Effective Concentration ◽  
Amino Acid Incorporation ◽  
Acid Incorporation ◽  
Minimal Effective Concentration

When diaphragms isolated from normal rats were incubated with a C14-amino acid the addition of epinephrine or norepinephrine decreased incorporation of C14 into muscle protein. The inhibition occurred whether epinephrine was added in vitro or administered in vivo. The minimal effective concentration of epinephrine in vitro was 0.1 µg/ml. When the glucose concentration in the medium was raised to 300 mg % or more the epinephrine induced inhibition of amino acid incorporation into muscle protein was no longer observed.

scholarly journals Impact of Y143 HIV-1 Integrase Mutations on Resistance to Raltegravir In Vitro and In Vivo

2009 ◽  
Vol 54 (1) ◽  
pp. 491-501 ◽  
Author(s):  
Olivier Delelis ◽  
Sylvain Thierry ◽  
Frédéric Subra ◽  
Françoise Simon ◽  
Isabelle Malet ◽  
...  
Keyword(s):  
Viral Genome ◽  
Effective Concentration ◽  
Coding Region ◽  
Delayed Emergence ◽  
Infected Cells ◽  
High Level ◽  
Emergence Of Resistance ◽  
Hiv 1

ABSTRACT Integrase (IN), the HIV-1 enzyme responsible for the integration of the viral genome into the chromosomes of infected cells, is the target of the recently approved antiviral raltegravir (RAL). Despite this drug's activity against viruses resistant to other antiretrovirals, failures of raltegravir therapy were observed, in association with the emergence of resistance due to mutations in the integrase coding region. Two pathways involving primary mutations on residues N155 and Q148 have been characterized. It was suggested that mutations at residue Y143 might constitute a third primary pathway for resistance. The aims of this study were to investigate the susceptibility of HIV-1 Y143R/C mutants to raltegravir and to determine the effects of these mutations on the IN-mediated reactions. Our observations demonstrate that Y143R/C mutants are strongly impaired for both of these activities in vitro. However, Y143R/C activity can be kinetically restored, thereby reproducing the effect of the secondary G140S mutation that rescues the defect associated with the Q148R/H mutants. A molecular modeling study confirmed that Y143R/C mutations play a role similar to that determined for Q148R/H mutations. In the viral replicative context, this defect leads to a partial block of integration responsible for a weak replicative capacity. Nevertheless, the Y143 mutant presented a high level of resistance to raltegravir. Furthermore, the 50% effective concentration (EC50) determined for Y143R/C mutants was significantly higher than that obtained with G140S/Q148R mutants. Altogether our results not only show that the mutation at position Y143 is one of the mechanisms conferring resistance to RAL but also explain the delayed emergence of this mutation.

scholarly journals In Vitro Interactions of Artemisinin with Atovaquone, Quinine, and Mefloquine against Plasmodium falciparum

2002 ◽  
Vol 46 (5) ◽  
pp. 1510-1515 ◽  
Author(s):  
S. Gupta ◽  
M. M. Thapar ◽  
W. H. Wernsdorfer ◽  
A. Björkman
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Interaction ◽  
In Vitro Culture ◽  
Effective Concentration ◽  
Interstrain Differences ◽  
Molar Ratios ◽  
The Mean ◽  
In Vitro Interactions

ABSTRACT The interactions of artemisinin with atovaquone, quinine, and mefloquine were investigated in three Plasmodium falciparum strains (strains F-32, FCR-3, and K-1) by an in vitro culture assay. The parasites were cultured for 48 h in the presence of different concentrations and proportions of two drugs at a time in a checkerboard design. The response parameters were determined, and the sums of the fractional inhibitory concentrations (ΣFICs) of the drug combinations were calculated for different degrees of inhibition (50% effective concentration [EC50], EC90, and EC99). Within therapeutically relevant molar ratios (19 to 200), the combination of quinine and artemisinin showed mean ΣFICs of 1.71 at the EC50, 0.36 at the EC90, and 0.13 at the EC99, indicating increasing synergism. Within the range of molar ratios of 4.3 to 50, the combination of mefloquine and artemisinin yielded mean ΣFCIs of 0.93, 0.44, and 0.31 at the EC50, EC90, and EC99, respectively, indicating synergism. The atovaquone combination showed additive activity to synergism at atovaquone/artemisinin proportions considered relevant to the in vivo situation, i.e., between 4.3 and 200, with the mean ΣFICs decreasing from 1.34 at the EC50 to 0.85 and 0.23 at the EC90 and EC99, respectively. Interstrain differences in the degree of drug interaction were seen with the three strains for all combinations. Synergism was most consistent with quinine.

scholarly journals In VitroActivities of a Wide Panel of Antifungal Drugs against Various Scopulariopsis and Microascus Species

2015 ◽  
Vol 59 (9) ◽  
pp. 5827-5829 ◽  
Author(s):  
Magdalena Skóra ◽  
Małgorzata Bulanda ◽  
Tomasz Jagielski
Keyword(s):  
Amphotericin B ◽  
Effective Concentration ◽  
Antifungal Drugs ◽  
Antifungal Effect ◽  
Content Type ◽  
Minimal Effective Concentration

ABSTRACTThein vitroactivities of 11 antifungal drugs against 68ScopulariopsisandMicroascusstrains were investigated. Amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, voriconazole, and ciclopirox showed no or poor antifungal effect. The best activities were exhibited by terbinafine and caspofungin, where the MIC and MEC (minimal effective concentration) ranges were 0.0313 to >16 μg/ml and 0.125 to 16 μg/ml, respectively. The MIC and MEC modes were both 1 µg/ml for terbinafine and caspofungin; the MIC50and MEC50were 1 µg/ml for both drugs, whereas the MIC90and MEC90were 4 µg/ml and 16 µg/ml, respectively.

Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5α-dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes

1994 ◽  
Vol 130 (6) ◽  
pp. 634-640 ◽  
Author(s):  
Takara Yamamoto ◽  
Takaya Tamura ◽  
Jo Kitawaki ◽  
Yoshio Osawa ◽  
Hiroji Okada
Keyword(s):  
Human Placenta ◽  
Uterine Leiomyoma ◽  
High Dose ◽  
Aromatase Activity ◽  
Dependent Manner ◽  
Chain Cleavage ◽  
Time Period ◽  
Suicide Inactivation

Yamamoto T, Tamura T, Kitawaki J, Osawa Y, Okada H. Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5α-dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes. Eur J Endocrinol 1994;130:634–40. ISSN 0804–4643 Norethindrone (NET; 17α-ethynyl-19-nortestosterone), a progestogen component of the contraceptive pill, irreversibly inhibits aromatase activity in human placental microsomes. However, it is known also to be aromatized in vitro and in vivo to produce a biologically very active estrogen called ethynylestradiol (EE2). It is therefore inappropriate to administer a high dose of NET to estrogendependent cancer patients for a prolonged time period. In this study, we focused on 5α-dihydronorethindrone (5α-DHNET), a metabolite of NET that is not aromatizable, and the inhibitory effects of 5α-DHNET on human placental and uterine leiomyoma microsomal aromatase and other steroid synthetases. 5α-Dihydronorethindrone showed weak affinity for both estrogen and progestogen receptors. It inhibited significantly human placental aromatase activity in a dose-dependent manner (Ki = 9.0 μmol/l; Kinact = 0.024/min), as well as that of uterine leiomyoma, but did not influence cholesterol side-chain cleavage or 17α-hydroxylase, 21-hydroxylase or 11β-hydroxylase activities. These results suggest that 5α-DHNET may be useful as an aromatase inhibitor, whose use in large doses is expected to reduce the size of estrogen-dependent tumors. Takara Yamamoto, Department of Obstetrics and Gynecology, Kawaramachi-Hirokoji, Kamikyo-Ku, Kyoto 602, Japan

2-Hydroxylation and O-methylation of oestrogens by human placenta in vivo

1987 ◽  
Vol 115 (2) ◽  
pp. 272-274 ◽  
Author(s):  
F. D. Berg ◽  
E. Kuss
Keyword(s):  
Human Placenta ◽  
Umbilical Artery ◽  
Umbilical Vein ◽  
Peripheral Vein ◽  
Methyl Transferase ◽  
Post Placental

Abstract. Concentrations of unconjugated and conjugated 2-hydroxyoestrogens and their 2-methylethers were determined by radioimmunoassay in serum obtained from the umbilical artery, umbilical vein, retroplacental space, and maternal peripheral vein at the time of delivery. The concentrations of unconjugated 2-hydroxyoestrogens and 2-methoxyoestrogens were found to be significantly higher in the post-placental vessels than in the pre-placental vessels. On the basis of the concentrations measured it was estimated that the placenta secretes about 1.4 nmol/min 2-hydroxyoestrogens and about 1.7 nmol/min of 2-methoxyoestrogens. The present in vivo findings confirm the placental 2-hydroxylase- and catechol-O-methyl-transferase activities previously demonstrated in vitro.

Excretion of 2- and 3-monomethyl ethers of 2-hydroxyestrogens in healthy male volunteers

1996 ◽  
Vol 135 (2) ◽  
pp. 193-197 ◽  
Author(s):  
Markus Banger ◽  
Christoph Hiemke ◽  
Margitta Haupt ◽  
Rudolf Knuppen
Keyword(s):  
In Vivo Studies ◽  
Estrogen Metabolism ◽  
Minor Importance ◽  
Healthy Male ◽  
Healthy Male Volunteers ◽  
Male Volunteers ◽  
Major Route ◽  
Excretion Rates

Banger M, Hiemke C, Haupt M, Knuppen R. Excretion of 2- and 3-monomethyl ethers of 2-hydroxyestrogens in healthy male volunteers. Eur J Endocrinol 1996;135:193–7. ISSN 0804–4643 The formation of catecholestrogens by 2-and 4-hydroxylation of monophenolic estrogens represents a major route of estrogen metabolism. In vitro and in vivo studies on catecholestrogens have shown that 2-hydroxylated catecholestrogens are primarily inactivated by O-methylation, while O-methylation of 4-hydroxylated estrogen is of minor importance. In the present study the in vivo production of isomeric 2- and 3-monomethyl ethers of 2-hydroxyestrogens was measured in 12 healthy omnivorous male volunteers aged 51 ± 4 years. The sum of estrone and 17β-estradiol, 2-hydroxyestrogens (sum of 2-hydroxyestrone and 2-hydroxyestradiol), 4-hydroxyestrogens (sum of 4-hydroxyestrone and 4-hydroxyestradiol) and the sum of the isomeric monomethyl ethers of 2-hydroxyestrone and 2-hydroxyestradiol were measured in 24-h urinary samples. The determinations included hydrolysis of steroid conjugates, separation by chromatographic steps and final quantification by radioimmunoassay. The specificity of the antibodies enabled differentiation between the isomeric monomethyl ethers. The mean urinary excretion rates were 8.8 ± 2.9 μg/24 h for estrone plus estradiol, 5.2 ± 2.4 μg/24 h for the 2-hydroxyestrogens and 1.3 ± 0.5 μg/24 h for the 4-hydroxyestrogens. The 2- and 3-monomethyl ethers of the 2-hydroxyestrogens were found in all individuals, with excretion rates of 5.8 ± 2.6 μg/24 h for 2-methoxyestrogens and 3.6 ± 1.1 μg/24 h for 2-hydroxyestrogen-3-methyl ethers. The findings indicated that 2-hydroxyestradiol is metabolized in vivo by 2-O-methylation and, to a lesser extent, by 3-O-methylation. Markus Banger, Department of Psychiatry, University of Essen, Virchowstr. 174, 45147 Essen, Germany

SECRETION OF C19-STEROIDS AND OESTROGENS IN THE POLYCYSTIC OVARY SYNDROME. OVARIAN STUDIES IN VIVO AND IN VITRO (INCLUDING STUDIES IN VITRO ON A COINCIDENTAL GRANULOSA CELL TUMOUR)

1968 ◽  
Vol 42 (2) ◽  
pp. 229-243 ◽  
Author(s):  
S. L. JEFFCOATE ◽  
R. V. BROOKS ◽  
D. R. LONDON ◽  
F. T. G. PRUNTY ◽  
P. RHODES
Keyword(s):  
Granulosa Cell ◽  
Polycystic Ovary ◽  
Ovarian Tissue ◽  
Cyst Fluid ◽  
Cell Tumour ◽  
High Yield ◽  
Granulosa Cell Tumour ◽  
Polycystic Ovaries

SUMMARY Ovarian metabolism of C19-steroids and oestrogens has been assessed at ovarian wedge resection in 22 patients with polycystic ovaries. There were marked variations between different patients. High concentrations of androstenedione were found in ovarian vein plasma in some patients, and always after stimulation with human pituitary follicle-stimulating hormone (HP-FSH) in vivo. Its contribution to the daily production of testosterone has been considered. No measurable amounts of testosterone or dehydroepiandrosterone were found. Oestradiol concentration was sometimes normal or above. Large amounts of androstenedione were generally isolated from cyst fluid. Occasionally testosterone was found and also epitestosterone after FSH. That concentrations of oestrogens in cyst fluid are low was confirmed, but sometimes higher levels were found after FSH. Slices of ovarian tissue generally converted progesterone or pregnenolone to androstenedione in high yield but conversion to oestrogen appeared to be low. However, the difficulty of making quantitative comparisons by this method, in the absence of knowledge of the sizes of the pools of endogenous steroids in the tissue, has been recognized. No evidence was found in any of the 18 cases examined for a lack of 3β-hydroxysteroid dehydrogenase. In vitro synthesis of epitestosterone by both normal and polycystic ovaries has been observed. A coincidental granulosa cell tumour in one patient synthesized testosterone in high yield.

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