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1.
Int J Cancer ; 122(9): 1958-65, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18183586

RESUMO

Environmental pollution with nitroaromatic compounds may pose health hazards. We have examined the tumorigenicity in female Sprague-Dawley rats of 2,7-dinitrofluorene (2,7-diNF) and 9-oxo-2,7-diNF administered by intraperitoneal (i.p.) and oral routes at 10 micromol/kg body weight, 3 times per week for 4 weeks. After i.p. treatment, the estimated median latency for the combined malignant and benign mammary tumors was decreased in 2,7-diNF- (p = 0.003) or 9-oxo-2,7-diNF-treated (p = 0.007), relative to vehicle-treated rats (42 or 64 vs. 80 weeks, respectively), whereas after oral dosing, there were no significant differences. At 90 weeks, the malignant mammary tumor incidence in 2,7-diNF-, 9-oxo-2,7-diNF- and vehicle-i.p. treated rats was 44 (p = 0.02 vs. vehicle-treated), 25 and 6%, respectively. Liver and mammary gland DNA was analyzed by HPLC combined with electrospray tandem mass spectrometry for the presence of a deoxyguanosine (dG-2,7-diNF) adduct and a deoxyadenosine (dA-2,7-diNF) adduct derived from 2,7-diNF, and a deoxyguanosine (dG-9-oxo-2,7-diNF) adduct derived from 9-oxo-2,7-diNF. Both dG-2,7-diNF and dA-2,7-diNF were detected in DNA of 2,7-diNF-treated rats, whereas only very low levels of dG-9-oxo-2,7-diNF were detected in DNA of 9-oxo-2,7-diNF-treated rats. After i.p. treatment, the dA-2,7-diNF level was higher (p < 0.01) in the mammary gland than liver (13.6 vs. 7.8 adducts/10(8) nucleotides). In the mammary gland, the dG-2,7-diNF level was higher (p < 0.05) after i.p. than oral dosing and also higher (p < 0.05) than in the liver (36 vs. 8.6 and vs. 9.1 adducts/10(8) nucleotides, respectively). The preferential display of carcinogenicity and genotoxicity in the mammary gland by low doses of 2,7-diNF signifies its potential relevance for environmental breast cancer.


Assuntos
Carcinógenos Ambientais/toxicidade , Poluentes Ambientais/toxicidade , Fluorenos/toxicidade , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/induzido quimicamente , Mutagênicos/toxicidade , Administração Oral , Animais , Ácido Ascórbico/farmacologia , Carcinógenos Ambientais/metabolismo , Cromatografia Líquida de Alta Pressão , Adutos de DNA/efeitos dos fármacos , Adutos de DNA/metabolismo , Desoxiguanosina/metabolismo , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/metabolismo , Feminino , Fluorenos/administração & dosagem , Fluorenos/metabolismo , Incidência , Injeções Intraperitoneais , Estimativa de Kaplan-Meier , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Mutagênicos/metabolismo , Compostos Nitrosos/toxicidade , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
2.
Food Chem Toxicol ; 46(7): 2451-8, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18486294

RESUMO

3,3'-diindolylmethane (DIM), derived from indole-3-carbinol (I3C), is used as a dietary supplement for its putative anticancer effects that include suppression of mammary tumor growth in female rats. The mechanism of action DIM may involve its interaction(s) with hepatic cytochromes P450 (CYPs) catalyzing oxidations of 17beta-estradiol (E2). Our study showed that DIM added to hepatic microsomes of female Sprague-Dawley rats was primarily a competitive inhibitor of beta-naphthoflavone (beta-NF)- or I3C-induced CYP1A1 probe activity, and a potent mixed or uncompetitive inhibitor of phenobarbital (PB)-induced CYP2B1 or CYP2B2 probe activity, respectively. Microsomal metabolites of DIM were tentatively identified as two mono-hydroxy isomers of DIM, each formed preferentially by CYP1A1- or CYP2B1/2-catalyzed reaction. Evaluation of the effects of co-treatment of rats with PB and DIM by a full factorial ANOVA showed that DIM decreased the PB-induced CYP2B1 and CYP2B2 mRNA expression levels, and the rates of 2- and 4-hydroxylation of E2, and total E2 metabolite formation. The results suggest that interactions of DIM, and/or its mono-hydroxy metabolites, with CYP2B1 and CYP2B2 found to occur in hepatic microsomes upon addition of DIM or co-treatment of rats with DIM affect the rates of relevant oxidations of E2, and potentially protect against estrogen-dependent tumorigenesis.


Assuntos
Anticarcinógenos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Indóis/farmacologia , Microssomos Hepáticos/enzimologia , RNA Mensageiro/metabolismo , Análise de Variância , Animais , Anticarcinógenos/administração & dosagem , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP2B1/antagonistas & inibidores , Citocromo P-450 CYP2B1/genética , Citocromo P-450 CYP2B1/metabolismo , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/genética , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Estradiol/metabolismo , Feminino , Técnicas In Vitro , Indóis/administração & dosagem , Indóis/química , Cinética , Microssomos Hepáticos/efeitos dos fármacos , Oxirredução , RNA Mensageiro/análise , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos , Esteroide Hidroxilases/antagonistas & inibidores , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo
3.
Eur J Cancer Prev ; 16(2): 130-41, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17297389

RESUMO

This study examined whether suppression of mammary gland carcinogenesis elicited by low doses of tamoxifen (TAM) can be enhanced by concomitant treatment of rats with indole-3-carbinol (I3C), a component of cruciferous vegetables and a dietary supplement used for its putative antiestrogenicity. Two weeks after one oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at 65 mg/kg body weight, female Sprague-Dawley rats started treatment with TAM (10 microg/rat) by subcutaneous injection, I3C (250 mg/kg body weight) by oral gavage, TAM+I3C or their respective vehicles three times per week, for up to 20 weeks. Significant increases in the median latency of malignant mammary tumors and decreases in the mean tumor mass per rat were due to TAM. Significant decreases in the mean tumor number per rat in TAM, I3C and TAM+I3C-treated rats indicated a cooperative effect of the two compounds. In both DMBA-initiated and uninitiated rats, significant increases in the ratios of liver to body weight in I3C and TAM+I3C-treated groups coincided with I3C-dependent increases of hepatic cytochrome P450 levels and activities (1A1, 1A2 and 2B1/2). The ratios of uterus to body weight decreased with the number of treatments and the decreases effected by TAM were greater than those by I3C. The levels of circulating estrone were increased in response to I3C treatment and were greater in DMBA-initiated rats than in uninitiated rats, which may contribute to the preventive effect of I3C. Chemoprevention may be accomplished through up-regulation of apoptotic enzyme (caspase) activities in the mammary gland or mammary tumors. Treatment with TAM, I3C or TAM+I3C had no effect on caspase-3&7, caspase-6, caspase-8 and caspase-9 activities in the mammary tumors or mammary gland of tumor-bearing rats or that of uninitiated rats. In the mammary gland of DMBA-initiated tumor-free rats, however, I3C treatment increased the levels of caspase-3&7 and caspase-9 activities, suggesting an I3C-mediated protective effect. Even though I3C alone is a much less effective suppressing agent of mammary carcinogenesis than TAM, I3C in combination with TAM does not weaken but may foster the benefits of chemoprevention with TAM.


Assuntos
Anticarcinógenos/uso terapêutico , Indóis/uso terapêutico , Neoplasias Mamárias Animais/prevenção & controle , Tamoxifeno/uso terapêutico , Animais , Quimioterapia Combinada , Feminino , Ratos , Ratos Sprague-Dawley
4.
Cancer Detect Prev ; 28(1): 72-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15041081

RESUMO

Indole-3-carbinol (I3C), present in cruciferous vegetables, and its major in vivo product 3,3'-diindolylmethane (DIM), have been reported to suppress estrogen-responsive cancers. This effect may be mediated through the modification of cytochrome P450 (CYP) complement and activities leading to estrogen detoxification. We examined the effects of a 4-day treatment of female Sprague-Dawley rats with DIM at 8.4 and 42 mg/kg body weight (bwt), on the hepatic CYP protein level, CYP1A1, 1A2, 2B1/2 and 3A1/2 probe activities and CYP-dependent metabolism of 17beta-estradiol (E2) and estrone (E1). At 42 mg/kg bwt, DIM effected a small increase (2.8-fold) in CYP1A1 activity, and at both dose levels it reduced CYP3A1/2 activity by approximately 40%. At the higher dose level, DIM decreased the rates of oxidation of E2 to 4-OH-E2, 4-OH-E1, 6alpha-OH-E2 and 6(alpha+beta)-OH-E1 by 39, 44, 71 and 60%, respectively, and E1 to 6(alpha+beta)-OH-E1 by 39%. These effects were considerably different from those of I3C reported by us previously. We also examined the effects of DIM and I3C on the hepatic microsomal metabolism of tamoxifen (TAM). Whereas metabolism of TAM was unaffected by DIM, formation of N-desmethyl-TAM (and its presumed derivative) was increased approximately 3-fold by I3C at 250 mg/kg bwt. Since N-desmethyl-TAM is transformed to a genotoxic metabolite, dietary exposure to I3C may enhance hepatic carcinogenicity of TAM in the rat. The differences between I3C and DIM in CYP-mediated activities and metabolism indicate that DIM is not a proximate intermediate in the mechanism of action of I3C.


Assuntos
Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Estrogênios/metabolismo , Indóis/farmacologia , Tamoxifeno/metabolismo , Análise de Variância , Animais , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/metabolismo , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Animais , Probabilidade , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sensibilidade e Especificidade
5.
J Natl Cancer Inst ; 96(14): 1099-104, 2004 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-15265972

RESUMO

BACKGROUND: Although the nonsteroidal antiestrogen tamoxifen is used as an adjuvant chemotherapeutic agent to treat hormone-dependent breast cancer and as a chemopreventive agent in women with elevated risk of breast cancer, it has also been reported to increase the risk of endometrial cancer. Reports of low levels of tamoxifen-DNA adducts in human endometrial tissue have suggested that tamoxifen induces endometrial cancer by a genotoxic mechanism. However, these findings have been controversial. We used electrospray ionization-tandem mass spectrometry (ES-MS/MS) and 32P-postlabeling analyses to investigate the presence of tamoxifen-DNA adducts in human endometrial tissue. METHODS: Endometrial DNA from eight tamoxifen-treated women and eight untreated women was hydrolyzed to nucleosides and assayed for (E)-alpha-(deoxyguanosin-N2-yl)-tamoxifen (dG-Tam) and (E)-alpha-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen (dG-desMeTam), the two major tamoxifen-DNA adducts that have been reported to be present in humans and/or experimental animals treated with tamoxifen, using on-line sample preparation coupled with high-performance liquid chromatography (HPLC) and ES-MS/MS. The same DNA samples were assayed for the presence of dG-Tam and dG-desMeTam by (32)P-postlabeling methodology, using two different DNA digestion and labeling protocols, followed by both thin-layer chromatography and HPLC. RESULTS: We did not detect either tamoxifen-DNA adduct by HPLC-ES-MS/MS analyses (limits of detection for dG-Tam and dG-desMeTam were two adducts per 10(9) nucleotides and two adducts per 10(8) nucleotides, respectively) or by 32P-postlabeling analyses (limit of detection for both adducts was one adduct per 10(9) nucleotides) in any of the endometrial DNA samples. CONCLUSION: The initiation of endometrial cancer by tamoxifen is probably not due to a genotoxic mechanism involving the formation of dG-Tam or dG-desMeTam.


Assuntos
Antineoplásicos Hormonais/metabolismo , Adutos de DNA/análise , Neoplasias do Endométrio/induzido quimicamente , Moduladores de Receptor Estrogênico/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Tamoxifeno/metabolismo , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Cromatografia Líquida de Alta Pressão , Adutos de DNA/isolamento & purificação , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/genética , Moduladores de Receptor Estrogênico/administração & dosagem , Moduladores de Receptor Estrogênico/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Radioisótopos de Fósforo , Cintilografia , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos
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