Induction of NAD(P)H quinone oxidoreductase and glutathione S-transferase activities in livers of female August-Copenhagen Irish rats treated chronically with estradiol: comparison with the Sprague–Dawley rat

Sánchez, Rosa I.; Mesía-Vela, Sonia; Kauffman, Frederick C.

doi:10.1016/j.jsbmb.2003.08.007

Cited by 22 publications

(15 citation statements)

References 41 publications

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“…The effects of PB on NQO1 and GST in liver were opposite to those on GPx and were in accord with the idea that regulation of expression of GPx differs from that of NQO1 and GST (Radjendirane et al, 1998;Esposito et al, 2000). It is also of considerable interest that administration of E 2 alone increases the level of antioxidant enzymes, a finding observed earlier by our group (Sanchez et al, 2003;Mesia-Vela et al, 2004). Moreover, the induction of NQO1 and GST in response to chronic treatment with E 2 seems to be specific for the ACI rat (Sanchez et al, 2003).…”

supporting

confidence: 87%

“…It is also of considerable interest that administration of E 2 alone increases the level of antioxidant enzymes, a finding observed earlier by our group (Sanchez et al, 2003;Mesia-Vela et al, 2004). Moreover, the induction of NQO1 and GST in response to chronic treatment with E 2 seems to be specific for the ACI rat (Sanchez et al, 2003). The stimulatory effect of PB administration alone or together with E 2 on NQO1 and GST activity suggests that PB induction of antioxidant enzymes may play a role in the protective effect of PB on E 2 -induced breast cancer.…”

supporting

confidence: 57%

“…Glucuronosyltransferase activity was assayed using a modification of a previously described method (Sanchez et al, 2003). The reaction mixture contained 1.0 mg of microsomal protein, 2 mM UDPGA, 5 mM MgC1 2 , 100 M [ 3 H]E 2 (0.15 Ci), and 50 mM Tris-HCl buffer, pH 8.5, in a final volume of 150 l. The reaction was initiated by the addition of UDPGA.…”

Section: Enzyme Assaysmentioning

confidence: 99%

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Phenobarbital Treatment Inhibits the Formation of Estradiol-Dependent Mammary Tumors in the August-Copenhagen Irish Rat

Mesía-Vela

Sánchez²,

Reuhl³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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Exposure of female August-Copenhagen Irish (ACI) rats for 28 weeks to 3 mg of estradiol (E 2 ) contained in cholesterol pellets elevated blood E 2 levels and caused palpable mammary tumors in all animals. Coadministration of phenobarbital (PB) in their drinking water reduced the incidence, number, and size of mammary tumors (MTs) but did not reduce blood E 2 levels. Inhibition of MTs by PB was accompanied by significant changes in total hepatic metabolism of E 2 measured in vitro. PB treatment caused approximately a 4-fold increase in hepatic metabolism of E 2 in control and E 2 -treated rats. The major NAD(P)H-dependent metabolites of E 2 were 2-OH-E 2 and estrone (E 1 ). PB, either alone or together with E 2 , increased microsomal 2-hydroxylation of E 2 ; formation of E 1 was either unaffected or decreased slightly. PB also increased microsomal metabolism of E 2 to minor metabolites (4-OH-E 2 , 6␣-OH-E 2 , 6␤-OH-E 2 , 14␣-OH-E 2 , 6-keto E 1 , and 2-OH-E 1 ) and reduced the formation of the E 2 -17␤-oleoyl ester and the E 2 3-and 17-glucuronides. In contrast, when given in combination with E 2 , PB increased the formation of both glucuronides. Cotreatment of animals with PB and E 2 increased activities of NAD(P)H:quinone oxidoreductase and glutathione S-transferase to a greater extent than either compound alone. Collectively, these results show that the multiple actions of PB on hepatic metabolism of E 2 , including induction of E 2 hydroxylation, glucuronidation, and antioxidant defense enzymes along with inhibition of E 2 esterification in livers of female ACI rats, accompany a marked reduction of E 2 -dependent mammary tumors in this model. (Conney et al., 1973). Treatment of rodents with PB induces the synthesis of hepatic microsomal enzymes that hydroxylate progesterone, estradiol (E 2 ), estrone (E 1 ), deoxycorticosterone, testosterone, ⌬ 4 -androstene-3,17-dione, and cortisol (reviewed by Zhu and Conney, 1998). Endogenous estrogens are hydroxylated at multiple positions by several hepatic and nonhepatic microsomal monooxygenase systems (reviewed by Martucci and Fishman, 1993;Zhu and Conney, 1998). The alteration of microsomal hydroxylation of steroids by PB is reflected in vivo by enhanced metabolism and altered actions of steroids. For example, pretreatment of rats with PB decreases the uterotropic action of E 2 and E 1 and enhances their metabolism in vivo (Levin et al., 1967(Levin et al., , 1968. Treatment of rats with PB also inhibits the growth-promoting effect of testosterone on the seminal vesicles (Levin et al., 1974) and decreases the anesthetic action of progesterone and deoxycorticosterone in rodents (Conney et al., 1966). Phenobarbital (PB) is a known inducer of microsomal hydroxylation of drugs and steroids in rodents and in humansOxidative stress arising from redox cycling of catechol estrogens formed during E 2 metabolism has been suggested as an important factor in initiation and progression of many cancers, including mammary carcinogenesis (Cavalieri et al., 1997;Cavalieri and ...

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supporting

confidence: 87%

supporting

confidence: 57%

Section: Enzyme Assaysmentioning

confidence: 99%

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Phenobarbital Treatment Inhibits the Formation of Estradiol-Dependent Mammary Tumors in the August-Copenhagen Irish Rat

Mesía-Vela

Sánchez²,

Reuhl³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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“…The juvenile rat model, commonly used in study of estrogenic activity, using 19-to 21-day-old female Sprague-Dawley rats, was selected (8). The organs of rats at this age are fully estrogen responsive, but the hormone is not yet being produced in the ovaries, so this rat model can offer a clear hormone background when studying SERM activity (32). Eight groups of immature female rats were treated daily with E 2 (0.1 mg/kg) or vehicle control, with or without X-SERMs (10 mg/kg), for 3 days.…”

Section: Induction Of Nqo1 In Liver Cellsmentioning

confidence: 99%

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

Dietz²,

Dunlap

et al. 2007

Molecular Cancer Therapeutics

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The benzothiophene selective estrogen receptor modulators (SERM) raloxifene and arzoxifene are in clinical use and clinical trials for chemoprevention of breast cancer and other indications. These SERMs are ''oxidatively labile'' and therefore have potential to activate antioxidant responsive element (ARE) transcription of genes for cytoprotective phase II enzymes such as NAD(P)Hdependent quinone oxidoreductase 1 (NQO1). To study this possible mechanism of cancer chemoprevention, a family of benzothiophene SERMs was developed with modulated redox activity, including arzoxifene and its metabolite desmethylarzoxifene (DMA). The relative antioxidant activity of these SERMs was assayed and correlated with induction of NQO1 in murine and human liver cells. DMA was found to induce NQO1 and to activate ARE more strongly than other SERMs, including raloxifene and 4-hydroxytamoxifen. Livers from female, juvenile rats treated for 3 days with estradiol and/or with the benzothiophene SERMs arzoxifene, DMA, and F-DMA showed substantial induction of NQO1 by the benzothiophene SERMs. No persuasive evidence in this assay or in MCF-7 breast cancer cells was obtained of a major role for the estrogen receptor in induction of NQO1 by the benzothiophene SERMs. These results suggest that arzoxifene might provide chemopreventive benefits over raloxifene and other SERMs via metabolism to DMA and stimulation of ARE-mediated induction of phase II enzymes. The correlation of SERM structure with antioxidant activity and NQO1 induction also suggests that oxidative bioactivation of SERMs may be modulated to enhance chemopreventive activity. [Mol Cancer Ther 2007;6(9):2418 -28]

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“…H quinone:oxidoreductase (NQO1) was measured by the reduction of cytochrome c (50 μM) in the presence of liver cytosol (1-5 μg protein), 10 μM menadione and 1 mM NADPH as described previously (Sanchez et al, 2003). Reactions were carried out in 1 ml of reagent at 25° C and the reduction of cytochrome c (50 μM) was monitored continuously at 550nm.…”

Section: Nad(p)h Quinone:oxidoreductase (Nqo1)-nad(p)mentioning

confidence: 99%

Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats

et al. 2008

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Administration of 0.4% clofibrate in the diet stimulated estradiol (E 2 )-induced mammary carcinogenesis in the August-Copenhagen Irish (ACI) rat without having an effect on serum levels of E 2 . This treatment stimulated by several-fold the NAD(P)H-dependent oxidative metabolism of E 2 and oleyl-CoA-dependent esterification of E 2 to 17β-oleyl-estradiol by liver microsomes. Glucuronidation of E 2 by microsomal glucuronosyltransferase was increased moderately. In contrast, the activity of NAD(P)H quinone reductase 1 (NQO1), a representative monofunctional phase 2 enzyme, was significantly decreased in liver cytosol of rats fed clofibrate. Decreases in hepatic NQO1 in livers of animals fed clofibrate were noted before the appearance of mammary tumors. E 2 was delivered in cholesterol pellets implanted in 7 to 8 week old female ACI rats. The animals received AIN-76A diet containing 0.4% clofibrate for 6, 12 or 28 weeks. Control animals received AIN-76A diet. Dietary clofibrate increased the number and size of palpable mammary tumors but did not alter the histopathology of the E 2 -induced mammary adenocarcinomas. Collectively, these results suggest that the stimulatory effect of clofibrate on hepatic esterification of E 2 with fatty acids coupled with the inhibition of protective phase 2 enzymes, may in part, enhance E 2 -dependent mammary carcinogenesis in the ACI rat model.

show abstract

Induction of NAD(P)H quinone oxidoreductase and glutathione S-transferase activities in livers of female August-Copenhagen Irish rats treated chronically with estradiol: comparison with the Sprague–Dawley rat

Cited by 22 publications

References 41 publications

Phenobarbital Treatment Inhibits the Formation of Estradiol-Dependent Mammary Tumors in the August-Copenhagen Irish Rat

Phenobarbital Treatment Inhibits the Formation of Estradiol-Dependent Mammary Tumors in the August-Copenhagen Irish Rat

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats

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