Dietary clofibrate inhibits induction of hepatic antioxidant enzymes by chronic estradiol in female ACI rats

Mesía-Vela, Sonia; Sánchez, Rosa I.; Reuhl, Kenneth R.; Conney, Allan H.; Kauffman, Frederick C.

doi:10.1016/j.tox.2004.03.009

Cited by 7 publications

(5 citation statements)

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“…Parallel to NQO1, increased mRNA expression of NRF2 only after 120 days of E2 treatment indicates NRF2-mediated upregulation of NQO1, suggests a possible adaptive response to reduce E2-quinones. Estrogen-mediated increase in NQO1 enzymatic activity after 6 and 12 weeks of treatment has been shown earlier in the same rat model (54). Furthermore, our time course study demonstrates that BHA or Vit C treatment increases NQO1 protein levels after 120 days of treatment and it remains high even after 240 days of co-treatment with E2 ( Figure 2B and C).…”

Section: Discussionsupporting

confidence: 83%

“…During this early neoplastic stage, most of the changes including genetic instability responsible for the initiation of carcinogenesis occur in the mammary tissue (51,52). The transient increase in NQO1 mRNA and protein expression after 120 days of estrogen treatment may be an adaptive response in an attempt to reduce E2-quinones (53,54). NRF2 mRNA expression was also unchanged up to 15 days , e, f and g indicate a P value ,0.05 between specific treatment group and control, between specific treatment group and E2 treatment, between specific treatment group and mammary tumor, between siNQO1 or siNRF2 and scrambled, between siNQO1 and siNQO1 þ E2, between siNRF2 and siNRF2 þ E2 and between dicumarol and dicumarol þ E2, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Induction of NAD(P)H-quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer

Singh

Bhat

2011

Carcinogenesis

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Exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature, evidence and our studies strongly support the role of estrogen metabolism-mediated oxidative stress in estrogen-induced breast carcinogenesis. We have recently demonstrated that antioxidants vitamin C and butylated hydroxyanisole (BHA) or estrogen metabolism inhibitor α-naphthoflavone (ANF) inhibit 17β-estradiol (E2)-induced mammary tumorigenesis in female ACI rats. The objective of the current study was to identify the mechanism of antioxidant-mediated protection against E2-induced DNA damage and mammary tumorigenesis. Female ACI rats were treated with E2 in the presence or absence of vitamin C or BHA or ANF for up to 240 days. Nuclear factor erythroid 2-related factor 2 (NRF2) and NAD(P)H-quinone oxidoreductase 1 (NQO1) were suppressed in E2-exposed mammary tissue and in mammary tumors after treatment of rats with E2 for 240 days. This suppression was overcome by co-treatment of rats with E2 and vitamin C or BHA. Time course studies indicate that NQO1 levels tend to increase after 4 months of E2 treatment but decrease on chronic exposure to E2 for 8 months. Vitamin C and BHA significantly increased NQO1 levels after 120 days. 8-Hydroxydeoxyguanosine (8-OHdG) levels were higher in E2-exposed mammary tissue and in mammary tumors compared with age-matched controls. Vitamin C or BHA treatment significantly decreased E2-mediated increase in 8-OHdG levels in the mammary tissue. In vitro studies using silencer RNA confirmed the role of NQO1 in prevention of oxidative DNA damage. Our studies further demonstrate that NQO1 upregulation by antioxidants is mediated through NRF2.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Induction of NAD(P)H-quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer

Singh

Bhat

2011

Carcinogenesis

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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: 86%

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

Mesía-Vela

Sánchez²,

Reuhl³

et al. 2006

J Pharmacol Exp Ther

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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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“…This includes the modulation of hepatic metabolism of estrogen and subsequent effects on mammary tumorigenesis. Kauffman's laboratory (32,33) has demonstrated that alteration of hepatic metabolism of E 2 significantly alters the mammary tumor in- cidence. Wilson and Reed (34) suggested that the species differences in susceptibility to estrogen-induced tumors may arise from distinctive hepatic metabolism of E 2 to 4E 2 in the ACI rat liver.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Oxidative DNA Damage by Bioactive Berry Components

Aiyer

Kichambare

Gupta

2008

Nutrition and Cancer

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The hormone 17ss-estradiol (E(2)) causes oxidative DNA damage via redox cycling of its metabolites such as 4-hydroxy estradiol (4E(2)). In this study, ACI rats (8 wk old) were fed either AIN-93M diet or diets supplemented with 0.5% each of mixed berries (strawberry, blueberry, blackberry, and red and black raspberry), blueberry alone (BB; 2.5%), or ellagic acid (EA; 400 ppm) from 2 wk prior to and up to 12 wk of E(2) treatment. The liver DNA was analyzed for the presence of 8-oxo-7,8-dihydroguanine (8-oxodG) and other polar adducts by 32P-postlabeling. Compared to sham treatment, E(2) significantly increased the levels of both 8-oxodG and P-1 subgroup (259% and 214%, respectively; P< 0.05). EA diet significantly reduced E(2)-induced levels of 8-oxodG, P-1, P-2, and PL-1 by 79, 63, 44, and 67%, respectively (P< 0.001). BB diet also significantly reduced the levels of P-1, P-2, and PL-1 subgroups by 77, 43, and 68%, respectively (P< 0.001). Mixed berries were, however, ineffective. In addition, aqueous extracts of berries (2%) and EA (100 microM) were tested for their efficacy in diminishing oxidative DNA adducts induced by redox cycling of 4E(2) catalyzed by copper chloride in vitro. EA was the most efficacious (90%), followed by extracts of red raspberry (70%), blueberry, and strawberry (50% each; P< 0.001).

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Dietary clofibrate inhibits induction of hepatic antioxidant enzymes by chronic estradiol in female ACI rats

Cited by 7 publications

References 37 publications

Induction of NAD(P)H-quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer

Induction of NAD(P)H-quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer

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

Prevention of Oxidative DNA Damage by Bioactive Berry Components

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