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1.
Toxicol Lett ; 303: 48-54, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30599193

RESUMO

Our goal was to study the effect of BP3 (benzophenone 3) in the follicular assembly and the potential involvement of Foxl2 pathway using whole ovary cultures. Ovaries were collected from Wistar rats at birth, treated in vitro with vehicle (0.01% DMSO), BP3 (5.8 nM, 276 nM, 576 nM and 876 nM) or ESR2 inhibitor (0.1 nM), and cultured for 7 days. Nest breakdown, follicular assembly and the expression of several regulators of these processes (p27, Foxl2, Sox9, Bmp2, Cyp19 and Fst) were evaluated. In vitro exposure to BP3 (5.8 nM) decreased the population of total oocytes, the number of nests per ovary and early primary follicles population. In addition, BP3 (5.8 nM) induced overexpression of Foxl2 mRNA levels through ESR2 but increased Fst mRNA levels independently from ESR2 or Foxl2. We also observed that the number of p27-positive oocytes was decreased after BP3 (5.8 nM). On the other hand, exposure to BP3-276 increased total oocytes, the number of nests per ovary and decreased primary follicles. In addition, BP3-276 induced no changes of Foxl2 mRNA levels through ESR2 but increased Fst mRNA levels independently from ESR2 or Foxl2. In conclusion, our study clearly shows that exposure to BP3 is to perturb the early events of germ cell development as showed here in whole ovary cultures.


Assuntos
Benzofenonas/toxicidade , Folículo Ovariano/efeitos dos fármacos , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Família 19 do Citocromo P450/genética , Família 19 do Citocromo P450/metabolismo , Feminino , Proteína Forkhead Box L2/genética , Proteína Forkhead Box L2/metabolismo , Regulação da Expressão Gênica , Células Germinativas/efeitos dos fármacos , Células Germinativas/crescimento & desenvolvimento , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Folículo Ovariano/citologia , Folículo Ovariano/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Técnicas de Cultura de Tecidos
2.
Appl Environ Microbiol ; 84(13)2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29728383

RESUMO

In this study, we identified a P450 enzyme (STH10) and an oxidoreductase (POR) from Thanatephorus cucumeris NBRC 6298 by a combination of transcriptome sequencing and heterologous expression in Pichia pastoris The biotransformation of 11-deoxycortisol was performed by using Pichia pastoris whole cells coexpressing sth10 and por, and the product analysis indicated that the STH10 enzyme possessed steroidal 19- and 11ß-hydroxylase activities. This is a novel fungal P450 enzyme with 19-hydroxylase activity, which is different from the known steroidal aromatase cytochrome P450 19 (CYP19) and CYP11B families of enzymes.IMPORTANCE Hydroxylation is one of the most important reactions in steroid functionalization; in particular, C-19 hydroxylation produces a key intermediate for the synthesis of 19-nor-steroid drugs without a C-19 angular methyl group in three chemoenzymatic steps, in contrast to the current industrial process, which uses 10 chemical reactions. However, hydroxylation of the C-19 angular methyl group remains a very challenging task due to the high level of steric resistance to the C-19 methyl group between the A and B rings. The present report describes a novel fungal P450 enzyme with 19-hydroxylase activity. This opens a new venue for searching effective biocatalysts for the useful process of steroidal C-19 hydroxylation, although further studies for better understanding of the structural basis of the regioselectivity and substrate specificity of this fungal steroidal 19-hydroxylase are warranted to facilitate the engineering of this enzyme for industrial applications.


Assuntos
Basidiomycota/enzimologia , Basidiomycota/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Esteroides/metabolismo , Basidiomycota/genética , Biotransformação , Cortodoxona/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Família 19 do Citocromo P450 , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Hidroxilação , Oxigenases de Função Mista/metabolismo , Pichia/genética , Pichia/metabolismo , Recombinação Genética , Metabolismo Secundário/genética , Esteroide Hidroxilases , Especificidade por Substrato
3.
J Cell Biochem ; 119(6): 4334-4338, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29266331

RESUMO

Transcript analysis is usually performed by costly, time-consuming, and expertise intensive methods, like real time-PCR, microarray, etc. However, they are not much feasible in low-input laboratories. Therefore, we implemented the reverse transcription loop-mediated isothermal amplification (RT-LAMP) as a means of mammalian transcript analysis. Particularly, RT-LAMP was developed for buffalo aromatase cytochrome P450 (CYP19) transcript, to study its expression in 3D-cultured buffalo granulosa cells, which were exposed to lipopolysaccharide (LPS). The CYP19-RT-LAMP assay rapidly identified the LPS-induced downregulation of the CYP19 gene within 30 min at 63°C in a water bath. The assay was visualized via unaided eye by observing the change in turbidity and fluorescence, which were decreased by increasing the LPS exposure time to granulosa cells. Overall, the developed CYP19-RT-LAMP assay provided a hope on the application of RT-LAMP for mammalian transcript analysis in low-input laboratories.


Assuntos
Família 19 do Citocromo P450/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células da Granulosa/enzimologia , Lipopolissacarídeos/toxicidade , Técnicas de Amplificação de Ácido Nucleico/métodos , Animais , Búfalos , Família 19 do Citocromo P450/genética , Feminino , Células da Granulosa/citologia
4.
J Therm Biol ; 69: 76-84, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29037408

RESUMO

In fish species with temperature-dependent sex determination (TSD) or genotypic sex determination plus temperature effects (GSD + TE), temperature can either affect sex differentiation or determine the sex. However, it is unknown if epigenetic control of cyp19a1a expression is critical for high temperature induced masculinization in the freshwater fish Nile tilapia. We analyzed the cyp19a1a DNA methylation levels in three age groups and found that they were lower in females than in males. At 8 months of age, males had DNA methylation levels of the cyp19a1a promoter that were almost twice as high as those of females. Exposure to high temperatures increased the cyp19a1a promoter DNA methylation levels from 30.87 ± 4.56% to 48.34 ± 0.92% (P = 0.035) in females and from 50.33 ± 7.38% to 51.66 ± 4.75% in males (P = 0.867). The increases in the cyp19a1a promoter DNA methylation levels were associated with the mRNA expression levels and might play a role in promoting gonadal differentiation in high temperature induced group females toward the male pathway. Western blot analysis revealed that the cyp19a1a protein expression levels in females significantly declined after high temperature treatment; only a slight decline was recorded in male fish. These results reveal that epigenetic control of cyp19a1a mRNA and protein expression is related to the environmental temperature and sex ratios in fish with TSD or GSD + TE.


Assuntos
Ciclídeos/genética , Família 19 do Citocromo P450/genética , Epigênese Genética , Proteínas de Peixes/genética , Processos de Determinação Sexual , Animais , Sequência de Bases , Ciclídeos/crescimento & desenvolvimento , Metilação de DNA , Feminino , Temperatura Alta , Masculino , Diferenciação Sexual
5.
Aging Cell ; 16(4): 825-836, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28544226

RESUMO

Although age-related ovarian failure in female mammals cannot be reversed, recent strategies have focused on improving reproductive capacity with age, and rapamycin is one such intervention that has shown a potential for preserving the ovarian follicle pool and preventing premature ovarian failure. However, the application is limited because of its detrimental effects on follicular development and ovulation during long-term treatment. Herein, we shortened the rapamycin administration to 2 weeks and applied the protocol to both young (8 weeks) and middle-aged (8 months) mouse models. Results showed disturbances in ovarian function during and shortly after treatment; however, all the treated animals returned to normal fertility 2 months later. Following natural mating, we observed prolongation of ovarian lifespan in both mouse models, with the most prominent effect occurring in mice older than 12 months. The effects of transient rapamycin treatment on ovarian lifespan were reflected in the preservation of primordial follicles, increases in oocyte quality, and improvement in the ovarian microenvironment. These data indicate that short-term rapamycin treatment exhibits persistent effects on prolonging ovarian lifespan no matter the age at initiation of treatment. In order not to disturb fertility in young adults, investigators should in the future consider applying the protocol later in life so as to delay menopause in women, and at the same time increase ovarian lifespan.


Assuntos
Envelhecimento/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Reprodução/genética , Sirolimo/farmacologia , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Biomarcadores/metabolismo , Microambiente Celular/efeitos dos fármacos , Família 17 do Citocromo P450/genética , Família 17 do Citocromo P450/metabolismo , Família 19 do Citocromo P450/genética , Família 19 do Citocromo P450/metabolismo , Ciclo Estral/efeitos dos fármacos , Ciclo Estral/genética , Feminino , Fertilidade/genética , Expressão Gênica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Oócitos/citologia , Oócitos/metabolismo , Folículo Ovariano/citologia , Folículo Ovariano/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fatores de Tempo
6.
Biomed Res Int ; 2017: 9738640, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28337462

RESUMO

The key mechanisms responsible for achievement of full reproductive and developmental capability in mammals are the differentiation and transformation of granulosa cells (GCs) during folliculogenesis, oogenesis, and oocyte maturation. Although the role of 17 beta-estradiol (E2) in ovarian activity is widely known, its effect on proliferative capacity, gap junction connection (GJC) formation, and GCs-luteal cells transformation requires further research. Therefore, the goal of this study was to assess the real-time proliferative activity of porcine GCs in vitro in relation to connexin (Cx), luteinizing hormone receptor (LHR), follicle stimulating hormone receptor (FSHR), and aromatase (CYP19A1) expression during short-term (168 h) primary culture. The cultured GCs were exposed to acute (at 96 h of culture) and/or prolonged (between 0 and 168 h of culture) administration of 1.8 and 3.6 µM E2. The relative abundance of Cx36, Cx37, Cx40, Cx43, LHR, FSHR, and CYP19A1 mRNA was measured. We conclude that the proliferation capability of GCs in vitro is substantially associated with expression of Cxs, LHR, FSHR, and CYP19A1. Furthermore, the GC-luteal cell transformation in vitro may be significantly accompanied by the proliferative activity of GCs in pigs.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células da Granulosa/metabolismo , Oogênese/efeitos dos fármacos , Animais , Diferenciação Celular/genética , Família 19 do Citocromo P450/biossíntese , Estradiol/administração & dosagem , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Humanos , Técnicas de Maturação in Vitro de Oócitos , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Oogênese/genética , Receptores do FSH/biossíntese , Receptores do FSH/genética , Receptores do LH/biossíntese , Receptores do LH/genética , Suínos
7.
PLoS One ; 11(12): e0168246, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27973579

RESUMO

Luman (also known as LZIP or CREB3) is a transcription factor and a member of the cAMP responsive element-binding (CREB) family proteins. Although Luman has been detected in apoptotic granulosa cells and disorganized atretic bodies, the physiological function of Luman in follicular development has not been reported. Our objective is to determine the role of Luman in folliculogenesis by knocking down Luman expression in mouse GCs (granulosa cells) using shRNA. Luman expression was successfully knocked down in mouse GCs at the mRNA and protein level, as confirmed by real-time quantitative PCR, western blot and immunofluorescence staining, respectively. Knockdown of Luman significantly decreased the concentrations of estradiol (E2) and progesterone (P4) in cell culture medium. Furthermore, Luman knockdown promoted cell proliferation but had no effect on cell apoptosis. To elucidate the regulatory mechanism underlying the effects of Luman knockdown on steroid synthesis and cell cycle, we measured the mRNA and protein expression levels of several related genes. The expression of Star, Cyp19a1, and Cyp1b1, which encode steroidogenic enzymes, was down-regulated, while that of Cyp11a1 and Runx2, which also encode steroidogenic enzymes, was up-regulated. The expression of the cell cycle factors Cyclin A1, Cyclin B1, Cyclin D2, and Cyclin E was significantly up-regulated. Among apoptosis-related genes, only Bcl-2 was down-regulated, while Caspase 3, Bax and p53 were not significantly affected, suggesting that Luman knockdown may regulate cell cycle activity and hormone secretion at the transcriptional and translational level in mouse GCs. The expression of two important genes associated with folliculogenesis in mouse GCs, Has2 and Ptgs2, were also significantly altered by Luman knockdown. In conclusion, the findings of this study indicate that Luman regulates mouse GCs modulation of steroid synthesis, cell cycle activity and other regulators of folliculogenesis.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Estradiol/biossíntese , Células da Granulosa/citologia , Progesterona/biossíntese , RNA Interferente Pequeno/genética , Animais , Apoptose , Ciclo Celular , Proliferação de Células , Separação Celular , Citocromo P-450 CYP1B1/metabolismo , Família 19 do Citocromo P450/metabolismo , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Células da Granulosa/metabolismo , Lentivirus/metabolismo , Camundongos , Microscopia Confocal , Fosfoproteínas/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real
8.
Science ; 354(6308): 102-106, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27846500

RESUMO

Natural enzymes contain highly evolved active sites that lead to fast rates and high selectivities. Although artificial metalloenzymes have been developed that catalyze abiological transformations with high stereoselectivity, the activities of these artificial enzymes are much lower than those of natural enzymes. Here, we report a reconstituted artificial metalloenzyme containing an iridium porphyrin that exhibits kinetic parameters similar to those of natural enzymes. In particular, variants of the P450 enzyme CYP119 containing iridium in place of iron catalyze insertions of carbenes into C-H bonds with up to 98% enantiomeric excess, 35,000 turnovers, and 2550 hours-1 turnover frequency. This activity leads to intramolecular carbene insertions into unactivated C-H bonds and intermolecular carbene insertions into C-H bonds. These results lift the restrictions on merging chemical catalysis and biocatalysis to create highly active, productive, and selective metalloenzymes for abiological reactions.


Assuntos
Biocatálise , Família 19 do Citocromo P450/química , Metaloproteínas/química , Família 19 do Citocromo P450/genética , Irídio/química , Cinética , Metaloproteínas/genética , Metano/análogos & derivados , Metano/química , Mutação , Porfirinas/química , Conformação Proteica , Estereoisomerismo
9.
Hum Reprod ; 31(7): 1522-30, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27165618

RESUMO

STUDY QUESTION: What are the direct effects and physiological role of anti-Müllerian hormone (AMH) during primate follicular development and function at specific stages of folliculogenesis? SUMMARY ANSWER: AMH actions in the primate ovary may be stage-dependent, directly promoting pre-antral follicle growth while inhibiting antral follicle maturation and dominant follicle selection. WHAT IS KNOWN ALREADY: AMH is expressed in the adult ovary, particularly in developing follicles. Studies in mice suggest that AMH suppresses pre-antral follicle growth in vitro, and inhibits primordial follicle recruitment and FSH-stimulated antral follicle steroidogenesis. STUDY DESIGN, SIZE, DURATION: For in vitro study, secondary follicles were isolated from ovaries of 12 rhesus macaques and cultured for 5 weeks. For in vivo study, intraovarian infusion was conducted on five monkeys for the entire follicular phase during two spontaneous menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: For in vitro study, individual follicles were cultured in a 5% O2 environment, in alpha minimum essential medium supplemented with recombinant human FSH. Follicles were randomly assigned to treatments of recombinant human AMH protein or neutralizing anti-human AMH antibody (AMH-Ab). Follicle survival, growth, steroid production, steroidogenic enzyme expression, and oocyte maturation were assessed. For in vivo study, ovaries were infused with control vehicle or AMH-Ab during the follicular phase of the menstrual cycle. Cycle length, serum steroid levels, and antral follicle growth were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: AMH exposure during culture weeks 0-3 (pre-antral stage) promoted, while AMH-Ab delayed, antrum formation of growing follicles compared with controls. AMH treatment during culture weeks 3-5 (antral stage) decreased (P < 0.05) estradiol (E2) production, as well as the mRNA expression of cytochrome P450 family 19 subfamily A polypeptide 1, by antral follicles relative to controls, whereas AMH-Ab increased (P < 0.05) follicular mRNA levels of the enzyme. Intraovarian infusion of AMH-Ab during the follicular phase of the menstrual cycle increased (P < 0.05) the average levels of serum E2 compared with those of the control cycles. Three of the five AMH-Ab-treated ovaries displayed multiple (n = 2-9) medium-to-large (2-8 mm) antral follicles at the mid-cycle E2 peak, whereas only one large (4-7 mm) antral follicle was observed in all monkeys during their control cycles. The average levels of serum progesterone were higher (P < 0.05) during the luteal phase of cycles following the AMH-Ab infusion relative to the vehicle infusion. LIMITATIONS, REASONS FOR CAUTION: The in vitro study of AMH actions on cultured individual macaque follicles was limited to the interval from the secondary to small antral stage. A sequential study design was used for in vivo experiments, which may limit the power of the study. WIDER IMPLICATIONS OF THE FINDINGS: The current study provides novel information on direct actions and role of AMH during primate follicular development, and selection of a dominant follicle by the late follicular phase of the menstrual cycle. We hypothesize that AMH acts positively on follicular growth during the pre-antral stage in primates, but negatively impacts antral follicle maturation, which is different from what is reported in the mouse model. STUDY FUNDING/COMPETING INTERESTS: NIH NICHD R01HD082208, NIH ORWH/NICHD K12HD043488 (BIRCWH), NIH OD P51OD011092 (ONPRC), Collins Medical Trust. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.


Assuntos
Hormônio Antimülleriano/farmacologia , Folículo Ovariano/efeitos dos fármacos , Animais , Hormônio Antimülleriano/sangue , Hormônio Antimülleriano/imunologia , Anticorpos Neutralizantes/farmacologia , Família 19 do Citocromo P450/metabolismo , Estradiol/biossíntese , Feminino , Macaca mulatta , Folículo Ovariano/crescimento & desenvolvimento , Progesterona/sangue , RNA Mensageiro/metabolismo , Distribuição Aleatória , Técnicas de Cultura de Tecidos
10.
Pharm Biol ; 54(11): 2404-2409, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27049656

RESUMO

CONTEXT: Albizia species are reported to exhibit many biological activities including antiovulatory properties in female rats and antispermatogenic and antiandrogenic activities in male rats. OBJECTIVE: The present study investigates the flavonoids of Albizia amara (Roxb.) B. Boivin (Fabaceae) leaves and evaluates their activity on gene expression of fertility and antioxidant glutathione-S-transferase-related genes of treated female mice in addition to their effect on DNA damage. MATERIALS AND METHODS: Plant materials were extracted by using 70% methanol for 48 h, the extract was chromatographed on a polyamide 6S column, each isolated compound was purified by using Sephadex LH-20 column; its structure was elucidated by chemical and spectral methods. Both the leaves extract and myricitrin (200, 30 mg/kg bw/d, respectively) were assayed for their effect on DNA damage in female mice after four weeks treatment using Comet assay. Their modulatory activity on gene expression of fertility (aromatase CYP19 and luteinizing hormone LH) and antioxidant glutathione-S-transferase (GST)-related genes of treated female mice were investigated by real-time PCR (qPCR). RESULTS: Quercetin-3-O-gentiobioside, myricitrin, quercetin-3-O-α-rhamnopyranoside, myricetin, quercetin and kaempferol were isolated and identified from the studied taxa. Myricitrin and the extract induced low rate of DNA damage (4.8% and 5%, respectively), compared with the untreated control (4.2%) and significantly down-regulated the expression of CYP19 and LH genes and up-regulated GST gene. DISCUSSION AND CONCLUSION: Our results highlight the potential effect of the leaves extract of Albizia amara and myricitrin as fertility-regulating phytoconstituents with ability to protect DNA from damage and cells from oxidative stress.


Assuntos
Albizzia/química , Dano ao DNA/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Animais , Família 19 do Citocromo P450/genética , Feminino , Flavonoides/isolamento & purificação , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glutationa Transferase/genética , Camundongos , Folhas de Planta/química
11.
J Pharm Pharmacol ; 68(4): 475-84, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26893163

RESUMO

OBJECTIVE: The effects of miroestrol (MR), an active phytoestrogen from Pueraria candollei var. mirifica, on expression of cancer-related genes were determined. METHODS: Seven-week-old female ICR mice (n = 5 each) were subcutaneously administered estradiol (E2, 0.5 mg/kg/day) or MR (0.5 or 5 mg/kg/day) daily for 7 days. Some were given ER or MR in combination with ß-naphthoflavone (BNF, 30 mg/kg/day) for the last 3 days. The expression of cancer-related genes including cytochrome P450 1A (Cyp1a), cytochrome P450 1B1 (Cyp1b1), aromatase P450 (Cyp19), NAD(P)H: quinone oxidoreductase 1 (Nqo1) and catechol-O-methyltransferase (Comt) were evaluated. KEY FINDINGS: In the presence of BNF, MR suppressed hepatic CYP1A1 activity and CYP1A2 activity, expression of CYP1B1 mRNA and expression of CYP1A1/2 and CYP1B1 protein. E2, by contrast, did not. MR restored expression levels of hepatic NQO1 and uterine COMT in BNF-treated mice. Furthermore, MR increased expression of uterine CYP19 to the same extent as E2. CONCLUSION: MR may be superior to E2 as it downregulates expression of CYP1. Moreover, MR normalized expression of both NQO1 and COMT, the protective enzymes, in murine liver and uteri. These results support the use of MR as an alternative supplement for menopausal women, MR having the extra benefit of reducing cancer risk.


Assuntos
Catecol O-Metiltransferase/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Família 19 do Citocromo P450/metabolismo , Terapia de Reposição de Estrogênios/métodos , Fígado/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fitoestrógenos/farmacologia , Esteroides/farmacologia , Útero/efeitos dos fármacos , beta-Naftoflavona/farmacologia , Animais , Catecol O-Metiltransferase/genética , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Família 19 do Citocromo P450/genética , Estradiol/farmacologia , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fígado/enzimologia , Camundongos Endogâmicos ICR , NAD(P)H Desidrogenase (Quinona)/genética , Neoplasias/induzido quimicamente , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/prevenção & controle , Fitoestrógenos/toxicidade , Esteroides/toxicidade , Útero/enzimologia
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