The effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on estrogen metabolism in MCF-7 breast cancer cells: Evidence for induction of a novel 17β-estradiol 4-hydroxylase

Spink, David C.; Hayes, Carrie L.; Young, Nina R.; Christou, Maro; Sutter, Carrie Hayes; Jefcoate, Colin R.; Gierthy, John F.

doi:10.1016/0960-0760(94)90037-x

Cited by 181 publications

(97 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another important factor is excessive formation of 4-OHE 1 (E 2 ) as a major metabolite of E 1 (E 2 ), catalyzed by CYP1B1 [30][31][32]. Minimization of estrogen-DNA adduct formation occurs when COMT is present at high levels because methoxylation of 4-OHE 1 (E 2 ) is one of the key elements in reducing adduct formation.…”

Section: Resultsmentioning

confidence: 99%

“…In extrahepatic tissues, cytochrome P450 (CYP)1A1 and CYP1B1 predominantly metabolize the natural estrogens E 1 and E 2 to 2-and 4-catechol estrogens (CE), respectively [30][31][32], which can be competitively oxidized to their respective semiquinones and quinones. In general, the CE are inactivated by conjugating reactions, such as glucuronidation and sulfation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Zahid

Saeed

et al. 2007

Free Radical Biology and Medicine

View full text Add to dashboard Cite

The association found between breast cancer development and prolonged exposure to estrogens suggests that this hormone is of etiologic importance in the causation of the disease. Studies on estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation and mutagenicity have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, with DNA forms depurinating adducts [4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua]. These adducts cause mutations leading to the initiation of breast cancer. Catechol-O-methyltransferase (COMT) is considered an important enzyme that protects cells from the genotoxicity and cytotoxicity of catechol estrogens, by preventing their conversion to quinones. The goal of the present study was to investigate the effect of COMT inhibition on the formation of depurinating estrogen-DNA adducts. Immortalized human breast epithelial MCF-10F cells were treated with 4-OHE 2 (0.2 or 0.5 μM) for 24 h at 120, 168, 216, and 264 h post-plating or one time at 1-30 μM 4-OHE 2 with or without the presence of COMT inhibitor (Ro41-0960). The culture media were collected at each point, extracted by solid-phase extraction and analyzed by HPLC connected with a multichannel electrochemical detector. The results demonstrate that MCF-10F cells oxidize 4-OHE 2 to E 1 (E 2 )-3,4-Q, which react with DNA to form the depurinating N3Ade and N7Gua adducts. The COMT inhibitor Ro41-0960 blocked the methoxylation of catechol estrogens, with concomitant 3-4 fold increases in the levels of the depurinating adducts. Thus, low activity of COMT leads to higher levels of depurinating estrogen-DNA adducts that can induce mutations and initiate cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Zahid

Saeed

et al. 2007

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…with respect to oestrogen metabolism as breast cancer is an oestrogen-dependent tumour. Dioxin induction of MCF-7 breast cancer cells resulted in marked NADPH-dependent 4-hydroxylation of 17fl-oestradiol which was not inhibited by an anti-CYP1A1 antibody [18] and was inhibited by an antibody raised against mouse P450EF [19], now identified as murine CYP1B 1 [20], suggesting that CYP1B 1 may contribute to the 4-hydroxylation of oestradiol.…”

Section: Discussionmentioning

confidence: 99%

Expression of cytochrome P450 CYP1B1 in breast cancer

et al. 1995

View full text Add to dashboard Cite

The expression of CYP1B1 has been identified in breast cancer using the reverse transcriptase-polymerase chain reaction and immunoblotting. CYP1B1 mRNA was expressed in the majority of breast tumours and immunoblotting of breast tumours identified a single protein band of molecular weight 60 kDa corresponding to the predicted molecular weight of human CYP1B1. This is the first study to identify CYP1B1 expression in a turnout where it may represent a previously unknown pathway for the metabolism of oestradiol and chemotherapeutic drugs.

show abstract

“…Metabolism of E 2 to 2-hydroxyestradiol is predominantly catalyzed by cytochrome P450 CYP1A1 (Roy et al, 1992;Spink et al, 1998) with some contribution by members of the CYP3A family (Hammond et al, 1997), while metabolism of E 2 to the 4-hydroxyestradiol is mainly a result of CYP1B1 activity (Spink et al, 1994;Hayes et al, 1996;Jefcoate et al, 2000). In liver, TCDD increases the levels of CYP1A1 and CYP1A2 relative to CYP1B1 (Walker et al, 1999), hence 2-hydroxylation predominates over 4-hydroxylation.…”

Section: Effects Of Gender and Sex Hormones In The Tcdd Dose-responsementioning

confidence: 99%

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

et al. 2005

View full text Add to dashboard Cite

ᮀTCDD and other polyhalogenated aromatic hydrocarbon ligands of the aryl hydrocarbon receptor (AHR) have been classically considered as non-genotoxic compounds because they fail to be directly mutagenic in either bacteria or most in vitro assay systems. They do so in spite of having repeatedly been linked to oxidative stress and to mutagenic and carcinogenic outcomes. Oxidative stress, on the other hand, has been used as a marker for the toxicity of dioxin and its congeners. We have focused this review on the connection between oxidative stress induction and the toxic effects of fetal and adult dioxin exposure, with emphasis on the large species difference in sensitivity to this agent. We examine the roles that the dioxin-inducible cytochromes P450s play in the cellular and toxicological consequences of dioxin exposure with emphasis on oxidative stress involvement. Many components of the health consequences resulting from dioxin exposure may be attributable to epigenetic mechanisms arising from prolonged reactive oxygen generation.

show abstract

The effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on estrogen metabolism in MCF-7 breast cancer cells: Evidence for induction of a novel 17β-estradiol 4-hydroxylase

Cited by 181 publications

References 34 publications

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

Expression of cytochrome P450 CYP1B1 in breast cancer

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

Contact Info

Product

Resources

About