Marisa Cabeza - Academia.edu (original) (raw)
Papers by Marisa Cabeza
Current Drug Targets, Oct 26, 2018
Considerable progress has been made in learning about the physiology and biochemistry of the seba... more Considerable progress has been made in learning about the physiology and biochemistry of the sebaceous glands and several of the diseases that affect this component of the skin. Of these diseases, acne has particular importance. Although it is associated with adolescence, because of the hormonal changes that take place in this stage, when it is severe it can cause depression. Moreover, in a considerable proportion of acne sufferers both adolescent and adult, it can produce tumors and deformation of the sebaceous glands. This seriously affects the sufferers to the point where it may limit their professional activities because they do not want to be seen in public. In this article we review several important issues related to the sebaceous gland, with the objective of contributing to advances in current treatments. The sebaceous gland is described as an intracrine organ, which can codify a number of different hormones and receptors. A detailed review is given of steroid metabolism in the skin, the presence of different hormone receptors, and hormone influence on lipogenesis at different ages. The mechanism of action of androgens and progestogens is analyzed in relation to lipogenesis carried out in the sebaceous glands. Several new steroidal compounds are proposed. Their mechanism of action has been elucidated and they have been shown to influence lipogenesis in sebaceous glands, modifying their structure and biochemistry. These molecules offer potential for new treatment options.
Canadian Journal of Physiology and Pharmacology, Jun 26, 2023
The main aim of this study was to determine the maximum tolerated dose (MTD) of estradiol, proges... more The main aim of this study was to determine the maximum tolerated dose (MTD) of estradiol, progesterone, and a mixture of both to restore normal sleep in a model of rats' menopause. The second purpose was to describe the in vitro activity of glutamate decarboxylase (GAD) in sleep-related brain areas in the presence or absence of sex hormones. Ovariectomy increased periodic awakenings compared to those determined for the SHAM group. The estradiol+progesterone treatment for ovariectomized rats was effective by the fifth week in decreasing arousal and achieving a similar sleep behavior to the SHAM control. Rats tolerated the estradiol, progesterone, and a mixture of both until the maximum planned dose (0.66 mg/kg and 4.4 mg/kg, respectively). The in vitro studies indicated that the presence of 17β-E2+P in the assay triggered the activity of GAD65 in the studied brain areas. RU486 blocked such activity; however, GAD67 activity was not blocked. A dose escalation model was determined; the MTD coincided with the maximum dose of ET and PT used. However, the EPT combination restored normal sleep without toxic effects. The in vitro model demonstrated that 17β-E2 plus P in the assay increased the activity of GAD65 in the brain tissues.
Social Science Research Network, 2021
EC Pharmacology and Toxicology, Apr 29, 2021
PubMed, 1997
We demonstrated for the first time that progesterone and 5 alpha-dihydroprogesterone stimulate [U... more We demonstrated for the first time that progesterone and 5 alpha-dihydroprogesterone stimulate [U-14C]glucose incorporation into lipids in gonadectomized female hamster flanking organs. We also found that cholesterol stearate is the major lipid synthesized female hamster flanking organs under progesterone and 5 alpha-dihydroprogesterone stimulation. In this manner, progesterone and 5 alpha-dihydroprogesterone alter the consistency of sebum from gonadectomized female glands.
PubMed, 2002
Androgens, particularly 5α-dihydrotestosterone (DHT) (1, Fig. 1), are required to maintain the si... more Androgens, particularly 5α-dihydrotestosterone (DHT) (1, Fig. 1), are required to maintain the size and function of the prostate and are thought to play a major role in the pathogenesis of benign prostatic hyperplasia (BPH) as well as other diseases such as: prostate cancer, hirsutism, ...
PubMed, 1998
In order to determine the uptake and the metabolism of [3H]T by the mycelium of Penicillium crust... more In order to determine the uptake and the metabolism of [3H]T by the mycelium of Penicillium crustosum, cultures of the fungi containing radiolabeled testosterone were developed at different pHs. Also, the metabolism of this androgen in the growth medium of the fungus was determined. Results show that the [3H]T was taken up by the mycelium at pHs 6, 7, 8 and 9. In addition, the presence of [3H]DHT in the incubation medium indicated the participation of 5 alpha-reductase. The maximal activities of this enzyme were determined at pHs 6 and 8, suggesting the presence of two isozymes: type 1 (pH 8), and type 2 (pH 6). Into the mycelium only [3H]T was identified, indicating that isozymes are produced by the fungus under testosterone stimuli.
PubMed, 1993
The role of testosterone and levonorgestrel action on the flank organ by measuring sebaceous glan... more The role of testosterone and levonorgestrel action on the flank organ by measuring sebaceous gland lipogenesis of female hamsters by the metabolic incorporation of 14C-glucose were investigated. Also, a partial characterization of the radiolabeled lipid fraction was obtained. The effects of in vivo steroids administration were evaluated by 14C-U-glucose metabolic incorporation into lipids by the female hamster flank organs in culture conditions, in the presence or absence of LNG and/or T in the incubation medium. The radioactive lipids were identified by thin layer chromatography. Levonorgestrel alone or together with testosterone on female hamster flank organs decreased the organ weight and sebum content compared with T-treatment alone. In culture conditions, a rapid and significant increase of radiolabeled glucose was observed with T. By contrast when LNG was present in the incubation medium, no differences in 14C-U-glucose incorporation were observed when compared with their controls. When T+LNG were added, a similar result to the obtained when using LNG alone was determined. Testosterone increased glycerides and free fatty acids but decreased polar lipids; whereas LNG did not have any effect in the relative proportions of 14C-U-glucose incorporated into the different classes of lipids, when it was compared with their controls. The results indicated that LNG abolished the increasing effect of 14C glucose incorporation caused by T and changed the lipid composition induced on female hamsters flank organs.
PubMed, 2000
Antiandrogens have high impact in medicine as they are compounds capable of decreasing the effect... more Antiandrogens have high impact in medicine as they are compounds capable of decreasing the effect of benign prostatic hyperplasia, cancer, and other androgen-dependent diseases that affect a large percentage of the male population in the world. [figure: see text] Dihydrotestosterone, a 5 alpha-reductase metabolite of testosterone, has been implicated as the responsible factor of these androgen abnormalities. This fact indicates that the logical step in the treatment of these diseases is the inhibition of this enzyme activity using molecules that compete selectively with its natural substrates. The study of the pharmacological effect of antiandrogens requires specific animal models using a large number of laboratory animals. On basis of this concept, presently there is a tendency to eliminate studies with animals. In this paper we report a new method for antiandrogenic evaluation using microbial transformations.
PubMed, 1998
Background: This paper describes the inhibitory effect produced by propranolol pre-treatment on l... more Background: This paper describes the inhibitory effect produced by propranolol pre-treatment on lipid synthesis in flank organs from intact, gonadectomized, and isoproterenol-treated male hamsters. Furthermore, the effect induced by the same treatments on gland sebum composition is reported. Methods: Different groups of male hamsters were injected daily with propranolol, isoproterenol or propranolol plus isoproterenol. Treatment-effect was evaluated determining the in vitro incorporation of radioactive acetate into lipids in hamster flank organs from intact and castrated animals. Additionally, radiolabeled lipids were isolated and identified using TLC and autoradiography as methods. Results: Results demonstrate that castration significantly decreases lipid synthesis in male hamster flank organs. In addition, propranolol treatment inhibits such synthesis in glands from intact, gonadectomized, and isoproterenol-treated animals. However, isoproterenol treatment was ineffective when compared to intact or gonadectomized control vehicle-treated animals. Lipid classes isolated and identified lipids either in castrated or in drug-treated animals were phospholipids, cholesterol, monoglycerides, fatty acids, waxes and cholesterol esters. Conclusions: Results indicate an inhibitory effect induced on lipid synthesis by beta-adrenergic receptor antagonists; however, beta-adrenergic agonists drugs do not stimulate it. Data suggest a permissive role of adrenergic hormones on lipid synthesis in intact and in gonadectomized animals. Furthermore, castration decreased the synthesis, suggesting that a tight coupling between beta-adrenergic receptors and androgen receptors may be a prerequisite for lipogenesis in this tissue. Pre-treatment does not modify sebum composition in gonadectomized animal glands. These data support the evidence that activation of beta-adrenergic receptors could be an independent factor in the lipid composition regulation process.
Steroids, Dec 1, 1997
In order to study lipid synthesis in female hamster flank organs during the estrous cycle, ghmds ... more In order to study lipid synthesis in female hamster flank organs during the estrous cycle, ghmds were obtained from different animals during d(ff~rent phases of the ~3'cle. Lipid metabolism ()f [u-laClglucose was studied under in vitro conditions. The radioactive lipids .[brmed, were extraeted j~om the glands and quant~'ed. An aliquot of the extract was submitted to TLC m isolate and ident~' the lipids'.[+)rnwd. Lo~id synthesis in the glands increased signtfieantly during estrous compared with the diestrous phase, suggesting the ip~lTuence of sex hormones on lipid metabolism in.[lank organs. The radioaetive lipids isolated and identified were: phospholipids, cholesterol, glycerides, waxes, and cholesterol esters'. The percentages ~)]" conversion .[?om [U-lUC]glueose to cholesterol esters were minor in extracts from glands ()[diestrous animals" as compared to estrous and proestrous animals, whereas glycerides and waxes increased sign~Hcantly in metestrous and diestrous animals. To verily, and evaluate the role (~[ estrogen and progesterone in lipid synthesis, three different groups of gonadectomized.[emale hamsters were injected daily with estradiol, progesterone, and 5~x-progesterone. Aj?er treatments, glands were incubated with [U-14C]glucose to determine the incorporation ~?[ radioactive glucose into lipids" under culture conditions. The radioactive lipids ©,nthesized were subsequently extracted and identified. The results showed that estrogen had no effect on in vitro [U-14C]glucose incorporation into lipids by flank organs, compared to the vehicle, whereas progesterone and 5e~-progesterone increased radioaetive Io~id synthesis by the glands" sign~[~cantly (p < 0.05), The radioactive lipids isolated and identi[~edjh~m extracts ~?f gonadectomized female hamster flunk organs were: phospholipids, cholesterol, triglycerides, waxes, and cholesterol esters. Gonadeemmy increased phospholipid synthesis and decreased that ~/ monoglycerides, diglycerides, and waxes. The percentages of conversion from [U-14C]glucose to cholesterol esters were higher q[ter progesterone and 5c~progesterone treatments than in vehicle and estrogen-treatments. Our data indicate that plwgesterone and 5a-progesterone-treatments inereased the in vitro [ U-N C]glucose incorporation into lipids in.[lank organs from gonadectomized female hamsters. Furtherntore, the major lipid o,nthesized by glands under these stimuli were cholesterol ~¢~ttty acids'. Thus, progesterone and 5e~-progesterone alter the consistency ~[ sebum .[/om gonadecmmized.[emale glands'.
Journal of Enzyme Inhibition and Medicinal Chemistry, Mar 25, 2014
Abstract The role of progesterone in women&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Abstract The role of progesterone in women&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins. The presence of a hydroxyl group at C-17 in the progesterone skeleton brings about a loss of progestational activity whereas acetylation induces a progestational effect. The incorporation of an ethynyl functional group to the testosterone framework results in a loss of androgenic activity with a concomitant enhancement of the progestational effect. On the other hand, an ester function at C-3 of dehydroepiandrosterone skeleton induces partial antagonism to the PR.
PubMed, Dec 1, 1999
The purpose of this work is to synthesize a pregnane derivative with a high antiandrogenic effect... more The purpose of this work is to synthesize a pregnane derivative with a high antiandrogenic effect or a high inhibitory activity for the enzyme 5 alpha-reductase type 2. Benign prostatic hyperplasia and prostate cancer are androgen dependent diseases which afflict a large percentage of the male population. Dihydrotestosterone 3, a 5 alpha-reductase metabolite of testosterone 2 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5 alpha-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new drugs. The advent of finasteride 22 "figure 5" a 5 alpha-reductase inhibitor, has greatly alleviated the symptoms associated with benign prostatic hyperplasia. On the other hand, the discovery of cyproterone acetate 4 "figure 2" alone or in combination with the antiandrogens flutamide 14 "figure 3" or bicalutamide 21 has greatly reduced the misery of prostate cancer. Prostate cancer kills about 40,000 men in the USA and approximately 400,000 prostatectomies are performed each year. In our laboratory we have recently synthesized ten new progesterone derivatives 17 alpha-acyloyloxy-6-halo (chloro, bromo) 16 beta-methyl-4, 6-pregnadiene-3, 20-diones (54a-54e and 55a-55e), "figure 10". These steroids were evaluated as antiandrogens and exhibited a much higher activity than the commercially available cyproterone acetate 4. The same compounds were also evaluated as 5 alpha-reductase inhibitors and showed a slightly higher inhibitory activity than that of finasteride 22, the drug of choice today for the treatment of benign prostatic hyperplasia In another study we synthesized several new 4-halo (bromo and chloro) 17 alpha-benzoyloxy and also 4-halo-17 alpha-acetoxy progesterone derivatives (58-63) "figure 13". These compounds were prepared from the commercially available 17 alpha-acetoxy progesterone 56. The pharmacological evaluation of these steroids "figure 14" indicated that the 17 alpha-benzoyloxy derivatives (4-chloro and bromo) 62 and 63 were very potent antiandrogens. On the other hand, the 4-halo (bromo and chloro) 17 alpha-acetoxy (58, 59) and the 17 alpha-benzoyloxy-4-chloro analog 63 showed a very high inhibitory activity for the enzyme 5 alpha-reductase type 2 "figure 15".
Oriental journal of chemistry, Jun 30, 2023
This study demonstrated the antiproliferative potential of several dehydroepiandrosterone derivat... more This study demonstrated the antiproliferative potential of several dehydroepiandrosterone derivatives 2a-b, 3a-f, and 4a-f in LNCaP cells. LNCaP cells were cultured in the presence of the vehicle, dihydrotestosterone, or testosterone plus 2a-b, 3a-f, 4a-f, or finasteride. At 24 h the 3-(4,5-dimethylthiazol-2-yl)-2,5-di phenyltetrazolium bromide-test was performed to determine cell proliferation. In addition, the kinetic of SRD5A1 in these cells was studied in the presence or absence of different concentrations of 2a. Testosterone and dihydrotestosterone increased the proliferation of LNCaP compared to the vehicle-treated cells. Furthermore, steroids 2a-b, 3a-f, and 4a-f decreased the number of viable cells compared to testosterone treatment. However, finasteride did not affect viability. LNCaP cells converted radiolabeled testosterone into dihydrotestosterone. This conversion was inhibited by high concentrations of 2a, while at a pM concentration, the conversion increased slightly, suggesting the presence of allosteric sites in SRD5A1. In conclusion, the three series of derivatives of dehydroepiandrosterone significantly decreased the number of viable LNCaP cells, therefore, showing therapeutic potential to treat metastatic prostate cancer.
ChemInform, May 2, 2006
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
PubMed, 2002
The conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT), plus the presence of 5 a... more The conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT), plus the presence of 5 alpha-reductase enzyme, which is responsible for this reduction, had been demonstrated in P. crustosum broth. This enzyme is also present in androgen-dependent animal and human tissues such as prostate and seminal vesicles. The increase in the conversion of T to DHT has been implicated in androgen-dependent diseases such as benign prostate hyperplasia and prostate cancer. The use of 5 alpha-reductase inhibitors could mitigate these illnesses by inhibiting the DHT-receptor complex formation. The purpose of this study is to determine the inhibition pattern of 5 alpha-reductase by finasteride and PM-9 in P. crustosum broth. Km and Vmax values were determined in the broth by Lineweaver-Burk plots using different testosterone concentrations. The Km value was 0.22 microM and Vmax 0.833 pmol of DHT/mg of mycelium/day. The inhibition pattern of finasteride and PM-9 was also determined by Lineweaver-Burk plot, using different concentrations of T and inhibitors. The results of this study show that both finasteride and PM-9 inhibit 5 alpha-reductase in a competitive manner.
PubMed, 2000
These results indicate that castration decreased the flank organ diameter and the weight of the s... more These results indicate that castration decreased the flank organ diameter and the weight of the seminal vesicles, whereas daily injection of testosterone restores them. However injections of finasteride together with testosterone inhibited the diameter of the flank organs, the weight of the seminal vesicles, and the conversion of testosterone to dihydrotestosterone. The four compounds tested inhibited flank organ diameter size and the weight of the seminal vesicles as compared to the testosterone-treated animals. On the other hand, none of these compounds suppressed the conversion of testosterone to dihydrotestosterone. These results suggest that the synthesized steroids compete with androgen receptors.
Current Drug Targets, Oct 26, 2018
Considerable progress has been made in learning about the physiology and biochemistry of the seba... more Considerable progress has been made in learning about the physiology and biochemistry of the sebaceous glands and several of the diseases that affect this component of the skin. Of these diseases, acne has particular importance. Although it is associated with adolescence, because of the hormonal changes that take place in this stage, when it is severe it can cause depression. Moreover, in a considerable proportion of acne sufferers both adolescent and adult, it can produce tumors and deformation of the sebaceous glands. This seriously affects the sufferers to the point where it may limit their professional activities because they do not want to be seen in public. In this article we review several important issues related to the sebaceous gland, with the objective of contributing to advances in current treatments. The sebaceous gland is described as an intracrine organ, which can codify a number of different hormones and receptors. A detailed review is given of steroid metabolism in the skin, the presence of different hormone receptors, and hormone influence on lipogenesis at different ages. The mechanism of action of androgens and progestogens is analyzed in relation to lipogenesis carried out in the sebaceous glands. Several new steroidal compounds are proposed. Their mechanism of action has been elucidated and they have been shown to influence lipogenesis in sebaceous glands, modifying their structure and biochemistry. These molecules offer potential for new treatment options.
Canadian Journal of Physiology and Pharmacology, Jun 26, 2023
The main aim of this study was to determine the maximum tolerated dose (MTD) of estradiol, proges... more The main aim of this study was to determine the maximum tolerated dose (MTD) of estradiol, progesterone, and a mixture of both to restore normal sleep in a model of rats' menopause. The second purpose was to describe the in vitro activity of glutamate decarboxylase (GAD) in sleep-related brain areas in the presence or absence of sex hormones. Ovariectomy increased periodic awakenings compared to those determined for the SHAM group. The estradiol+progesterone treatment for ovariectomized rats was effective by the fifth week in decreasing arousal and achieving a similar sleep behavior to the SHAM control. Rats tolerated the estradiol, progesterone, and a mixture of both until the maximum planned dose (0.66 mg/kg and 4.4 mg/kg, respectively). The in vitro studies indicated that the presence of 17β-E2+P in the assay triggered the activity of GAD65 in the studied brain areas. RU486 blocked such activity; however, GAD67 activity was not blocked. A dose escalation model was determined; the MTD coincided with the maximum dose of ET and PT used. However, the EPT combination restored normal sleep without toxic effects. The in vitro model demonstrated that 17β-E2 plus P in the assay increased the activity of GAD65 in the brain tissues.
Social Science Research Network, 2021
EC Pharmacology and Toxicology, Apr 29, 2021
PubMed, 1997
We demonstrated for the first time that progesterone and 5 alpha-dihydroprogesterone stimulate [U... more We demonstrated for the first time that progesterone and 5 alpha-dihydroprogesterone stimulate [U-14C]glucose incorporation into lipids in gonadectomized female hamster flanking organs. We also found that cholesterol stearate is the major lipid synthesized female hamster flanking organs under progesterone and 5 alpha-dihydroprogesterone stimulation. In this manner, progesterone and 5 alpha-dihydroprogesterone alter the consistency of sebum from gonadectomized female glands.
PubMed, 2002
Androgens, particularly 5α-dihydrotestosterone (DHT) (1, Fig. 1), are required to maintain the si... more Androgens, particularly 5α-dihydrotestosterone (DHT) (1, Fig. 1), are required to maintain the size and function of the prostate and are thought to play a major role in the pathogenesis of benign prostatic hyperplasia (BPH) as well as other diseases such as: prostate cancer, hirsutism, ...
PubMed, 1998
In order to determine the uptake and the metabolism of [3H]T by the mycelium of Penicillium crust... more In order to determine the uptake and the metabolism of [3H]T by the mycelium of Penicillium crustosum, cultures of the fungi containing radiolabeled testosterone were developed at different pHs. Also, the metabolism of this androgen in the growth medium of the fungus was determined. Results show that the [3H]T was taken up by the mycelium at pHs 6, 7, 8 and 9. In addition, the presence of [3H]DHT in the incubation medium indicated the participation of 5 alpha-reductase. The maximal activities of this enzyme were determined at pHs 6 and 8, suggesting the presence of two isozymes: type 1 (pH 8), and type 2 (pH 6). Into the mycelium only [3H]T was identified, indicating that isozymes are produced by the fungus under testosterone stimuli.
PubMed, 1993
The role of testosterone and levonorgestrel action on the flank organ by measuring sebaceous glan... more The role of testosterone and levonorgestrel action on the flank organ by measuring sebaceous gland lipogenesis of female hamsters by the metabolic incorporation of 14C-glucose were investigated. Also, a partial characterization of the radiolabeled lipid fraction was obtained. The effects of in vivo steroids administration were evaluated by 14C-U-glucose metabolic incorporation into lipids by the female hamster flank organs in culture conditions, in the presence or absence of LNG and/or T in the incubation medium. The radioactive lipids were identified by thin layer chromatography. Levonorgestrel alone or together with testosterone on female hamster flank organs decreased the organ weight and sebum content compared with T-treatment alone. In culture conditions, a rapid and significant increase of radiolabeled glucose was observed with T. By contrast when LNG was present in the incubation medium, no differences in 14C-U-glucose incorporation were observed when compared with their controls. When T+LNG were added, a similar result to the obtained when using LNG alone was determined. Testosterone increased glycerides and free fatty acids but decreased polar lipids; whereas LNG did not have any effect in the relative proportions of 14C-U-glucose incorporated into the different classes of lipids, when it was compared with their controls. The results indicated that LNG abolished the increasing effect of 14C glucose incorporation caused by T and changed the lipid composition induced on female hamsters flank organs.
PubMed, 2000
Antiandrogens have high impact in medicine as they are compounds capable of decreasing the effect... more Antiandrogens have high impact in medicine as they are compounds capable of decreasing the effect of benign prostatic hyperplasia, cancer, and other androgen-dependent diseases that affect a large percentage of the male population in the world. [figure: see text] Dihydrotestosterone, a 5 alpha-reductase metabolite of testosterone, has been implicated as the responsible factor of these androgen abnormalities. This fact indicates that the logical step in the treatment of these diseases is the inhibition of this enzyme activity using molecules that compete selectively with its natural substrates. The study of the pharmacological effect of antiandrogens requires specific animal models using a large number of laboratory animals. On basis of this concept, presently there is a tendency to eliminate studies with animals. In this paper we report a new method for antiandrogenic evaluation using microbial transformations.
PubMed, 1998
Background: This paper describes the inhibitory effect produced by propranolol pre-treatment on l... more Background: This paper describes the inhibitory effect produced by propranolol pre-treatment on lipid synthesis in flank organs from intact, gonadectomized, and isoproterenol-treated male hamsters. Furthermore, the effect induced by the same treatments on gland sebum composition is reported. Methods: Different groups of male hamsters were injected daily with propranolol, isoproterenol or propranolol plus isoproterenol. Treatment-effect was evaluated determining the in vitro incorporation of radioactive acetate into lipids in hamster flank organs from intact and castrated animals. Additionally, radiolabeled lipids were isolated and identified using TLC and autoradiography as methods. Results: Results demonstrate that castration significantly decreases lipid synthesis in male hamster flank organs. In addition, propranolol treatment inhibits such synthesis in glands from intact, gonadectomized, and isoproterenol-treated animals. However, isoproterenol treatment was ineffective when compared to intact or gonadectomized control vehicle-treated animals. Lipid classes isolated and identified lipids either in castrated or in drug-treated animals were phospholipids, cholesterol, monoglycerides, fatty acids, waxes and cholesterol esters. Conclusions: Results indicate an inhibitory effect induced on lipid synthesis by beta-adrenergic receptor antagonists; however, beta-adrenergic agonists drugs do not stimulate it. Data suggest a permissive role of adrenergic hormones on lipid synthesis in intact and in gonadectomized animals. Furthermore, castration decreased the synthesis, suggesting that a tight coupling between beta-adrenergic receptors and androgen receptors may be a prerequisite for lipogenesis in this tissue. Pre-treatment does not modify sebum composition in gonadectomized animal glands. These data support the evidence that activation of beta-adrenergic receptors could be an independent factor in the lipid composition regulation process.
Steroids, Dec 1, 1997
In order to study lipid synthesis in female hamster flank organs during the estrous cycle, ghmds ... more In order to study lipid synthesis in female hamster flank organs during the estrous cycle, ghmds were obtained from different animals during d(ff~rent phases of the ~3'cle. Lipid metabolism ()f [u-laClglucose was studied under in vitro conditions. The radioactive lipids .[brmed, were extraeted j~om the glands and quant~'ed. An aliquot of the extract was submitted to TLC m isolate and ident~' the lipids'.[+)rnwd. Lo~id synthesis in the glands increased signtfieantly during estrous compared with the diestrous phase, suggesting the ip~lTuence of sex hormones on lipid metabolism in.[lank organs. The radioaetive lipids isolated and identified were: phospholipids, cholesterol, glycerides, waxes, and cholesterol esters'. The percentages ~)]" conversion .[?om [U-lUC]glueose to cholesterol esters were minor in extracts from glands ()[diestrous animals" as compared to estrous and proestrous animals, whereas glycerides and waxes increased sign~Hcantly in metestrous and diestrous animals. To verily, and evaluate the role (~[ estrogen and progesterone in lipid synthesis, three different groups of gonadectomized.[emale hamsters were injected daily with estradiol, progesterone, and 5~x-progesterone. Aj?er treatments, glands were incubated with [U-14C]glucose to determine the incorporation ~?[ radioactive glucose into lipids" under culture conditions. The radioactive lipids ©,nthesized were subsequently extracted and identified. The results showed that estrogen had no effect on in vitro [U-14C]glucose incorporation into lipids by flank organs, compared to the vehicle, whereas progesterone and 5e~-progesterone increased radioaetive Io~id synthesis by the glands" sign~[~cantly (p < 0.05), The radioactive lipids isolated and identi[~edjh~m extracts ~?f gonadectomized female hamster flunk organs were: phospholipids, cholesterol, triglycerides, waxes, and cholesterol esters. Gonadeemmy increased phospholipid synthesis and decreased that ~/ monoglycerides, diglycerides, and waxes. The percentages of conversion from [U-14C]glucose to cholesterol esters were higher q[ter progesterone and 5c~progesterone treatments than in vehicle and estrogen-treatments. Our data indicate that plwgesterone and 5a-progesterone-treatments inereased the in vitro [ U-N C]glucose incorporation into lipids in.[lank organs from gonadectomized female hamsters. Furtherntore, the major lipid o,nthesized by glands under these stimuli were cholesterol ~¢~ttty acids'. Thus, progesterone and 5e~-progesterone alter the consistency ~[ sebum .[/om gonadecmmized.[emale glands'.
Journal of Enzyme Inhibition and Medicinal Chemistry, Mar 25, 2014
Abstract The role of progesterone in women&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Abstract The role of progesterone in women&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins. The presence of a hydroxyl group at C-17 in the progesterone skeleton brings about a loss of progestational activity whereas acetylation induces a progestational effect. The incorporation of an ethynyl functional group to the testosterone framework results in a loss of androgenic activity with a concomitant enhancement of the progestational effect. On the other hand, an ester function at C-3 of dehydroepiandrosterone skeleton induces partial antagonism to the PR.
PubMed, Dec 1, 1999
The purpose of this work is to synthesize a pregnane derivative with a high antiandrogenic effect... more The purpose of this work is to synthesize a pregnane derivative with a high antiandrogenic effect or a high inhibitory activity for the enzyme 5 alpha-reductase type 2. Benign prostatic hyperplasia and prostate cancer are androgen dependent diseases which afflict a large percentage of the male population. Dihydrotestosterone 3, a 5 alpha-reductase metabolite of testosterone 2 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5 alpha-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new drugs. The advent of finasteride 22 "figure 5" a 5 alpha-reductase inhibitor, has greatly alleviated the symptoms associated with benign prostatic hyperplasia. On the other hand, the discovery of cyproterone acetate 4 "figure 2" alone or in combination with the antiandrogens flutamide 14 "figure 3" or bicalutamide 21 has greatly reduced the misery of prostate cancer. Prostate cancer kills about 40,000 men in the USA and approximately 400,000 prostatectomies are performed each year. In our laboratory we have recently synthesized ten new progesterone derivatives 17 alpha-acyloyloxy-6-halo (chloro, bromo) 16 beta-methyl-4, 6-pregnadiene-3, 20-diones (54a-54e and 55a-55e), "figure 10". These steroids were evaluated as antiandrogens and exhibited a much higher activity than the commercially available cyproterone acetate 4. The same compounds were also evaluated as 5 alpha-reductase inhibitors and showed a slightly higher inhibitory activity than that of finasteride 22, the drug of choice today for the treatment of benign prostatic hyperplasia In another study we synthesized several new 4-halo (bromo and chloro) 17 alpha-benzoyloxy and also 4-halo-17 alpha-acetoxy progesterone derivatives (58-63) "figure 13". These compounds were prepared from the commercially available 17 alpha-acetoxy progesterone 56. The pharmacological evaluation of these steroids "figure 14" indicated that the 17 alpha-benzoyloxy derivatives (4-chloro and bromo) 62 and 63 were very potent antiandrogens. On the other hand, the 4-halo (bromo and chloro) 17 alpha-acetoxy (58, 59) and the 17 alpha-benzoyloxy-4-chloro analog 63 showed a very high inhibitory activity for the enzyme 5 alpha-reductase type 2 "figure 15".
Oriental journal of chemistry, Jun 30, 2023
This study demonstrated the antiproliferative potential of several dehydroepiandrosterone derivat... more This study demonstrated the antiproliferative potential of several dehydroepiandrosterone derivatives 2a-b, 3a-f, and 4a-f in LNCaP cells. LNCaP cells were cultured in the presence of the vehicle, dihydrotestosterone, or testosterone plus 2a-b, 3a-f, 4a-f, or finasteride. At 24 h the 3-(4,5-dimethylthiazol-2-yl)-2,5-di phenyltetrazolium bromide-test was performed to determine cell proliferation. In addition, the kinetic of SRD5A1 in these cells was studied in the presence or absence of different concentrations of 2a. Testosterone and dihydrotestosterone increased the proliferation of LNCaP compared to the vehicle-treated cells. Furthermore, steroids 2a-b, 3a-f, and 4a-f decreased the number of viable cells compared to testosterone treatment. However, finasteride did not affect viability. LNCaP cells converted radiolabeled testosterone into dihydrotestosterone. This conversion was inhibited by high concentrations of 2a, while at a pM concentration, the conversion increased slightly, suggesting the presence of allosteric sites in SRD5A1. In conclusion, the three series of derivatives of dehydroepiandrosterone significantly decreased the number of viable LNCaP cells, therefore, showing therapeutic potential to treat metastatic prostate cancer.
ChemInform, May 2, 2006
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
PubMed, 2002
The conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT), plus the presence of 5 a... more The conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT), plus the presence of 5 alpha-reductase enzyme, which is responsible for this reduction, had been demonstrated in P. crustosum broth. This enzyme is also present in androgen-dependent animal and human tissues such as prostate and seminal vesicles. The increase in the conversion of T to DHT has been implicated in androgen-dependent diseases such as benign prostate hyperplasia and prostate cancer. The use of 5 alpha-reductase inhibitors could mitigate these illnesses by inhibiting the DHT-receptor complex formation. The purpose of this study is to determine the inhibition pattern of 5 alpha-reductase by finasteride and PM-9 in P. crustosum broth. Km and Vmax values were determined in the broth by Lineweaver-Burk plots using different testosterone concentrations. The Km value was 0.22 microM and Vmax 0.833 pmol of DHT/mg of mycelium/day. The inhibition pattern of finasteride and PM-9 was also determined by Lineweaver-Burk plot, using different concentrations of T and inhibitors. The results of this study show that both finasteride and PM-9 inhibit 5 alpha-reductase in a competitive manner.
PubMed, 2000
These results indicate that castration decreased the flank organ diameter and the weight of the s... more These results indicate that castration decreased the flank organ diameter and the weight of the seminal vesicles, whereas daily injection of testosterone restores them. However injections of finasteride together with testosterone inhibited the diameter of the flank organs, the weight of the seminal vesicles, and the conversion of testosterone to dihydrotestosterone. The four compounds tested inhibited flank organ diameter size and the weight of the seminal vesicles as compared to the testosterone-treated animals. On the other hand, none of these compounds suppressed the conversion of testosterone to dihydrotestosterone. These results suggest that the synthesized steroids compete with androgen receptors.
This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A... more This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds , as well as the new drugs, principally inhibitors of 5α-reductase.