Cytochrome P450 1B1–Mediated Estrogen Metabolism Results in Estrogen-Deoxyribonucleoside Adduct Formation

Belous, Alexandra R.; Hachey, David L.; Dawling, Sheila; Roodi, Nady; Parl, Fritz F.

doi:10.1158/0008-5472.can-06-2133

Cited by 78 publications

(68 citation statements)

References 41 publications

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“…Its predominant 4-hydroxylation of estrogen (6) results in the production of the ultimate carcinogenic metabolite, the depurinating quinone, as well as reactive oxygen species as reviewed by Cavalieri et al (14). It has recently been shown in vitro that CYP1B1 is the enzyme involved in the metabolism of estradiol to guanine and adenine adduct forming compounds, supporting its involvement in mammary carcinogenesis (15). Following oxidative metabolism and the activation by phase I enzymes, the phase II enzymes mediate detoxification of the reactive phase I metabolites.…”

Section: Introductionmentioning

confidence: 96%

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Emburgh

Hu²,

Levine³

et al. 2008

Oncol Rep

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Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age ≤60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an

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Section: Introductionmentioning

confidence: 96%

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Emburgh

Hu²,

Levine³

et al. 2008

Oncol Rep

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“…The extent of CYP1B1 expression responsible for the formation of 4-OHE 2 , hence, seems to be a critical determinant of the oxidative metabolism and toxicity of estrogen in mammary cells. The reactive quinone derived from 4-OHE 2 was reported to produce depurinating DNA adducts, such as 4-OHE 2 -N 7 -guanine and 4-OHE 2 -N 3 -adenine (9). Notably, the levels of 4-OHE 2 and the protein adducts of its reactive quinone metabolite were detected in the human breast tumor biopsies at significantly higher levels than those in the normal breast tissues (10).…”

Section: Introductionmentioning

confidence: 98%

4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of IκB Kinase: Potential Role of Reactive Oxygen Species

Park

Kim

et al. 2009

Cancer Research

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Estrogen is converted by cytochrome P450 1B1 to 4-hydroxyestradiol (4-OHE 2 ), a putative carcinogenic metabolite of estrogen. This catechol estrogen metabolite is oxidized further to produce a reactive quinone via semiquinone. Redox cycling between 4-OHE 2 and its quinoid generates reactive oxygen species (ROS). ROS not only causes oxidative DNA damage but also promotes neoplastic transformation of initiated cells. In the present study, 4-OHE 2 induced anchorageindependent colony formation in human mammary epithelial cells (MCF-10A). MCF-10A cells treated with 4-OHE 2 exhibited increased accumulation of intracellular ROS. The antioxidant N-acetyl-L-cysteine inhibited the neoplastic transformation induced by 4-OHE 2 . ROS overproduced by 4-OHE 2 increased the nuclear translocation of nuclear factor-KB (NF-KB) and its DNA binding through induction of IKB kinase A (IKKA) and IKKB activities. The inhibition of the IKK activities with Bay 11-7082 significantly reduced the anchorage-independent growth induced by 4-OHE 2 . The 4-OHE 2 -induced activation of extracellular signal-regulated kinase and Akt resulted in enhanced IKK activities and phosphorylation of IKBA, thereby inducing NF-KB activation and anchorage-independent growth of MCF-10A cells. In conclusion, ROS, concomitantly overproduced during redox cycling of 4-OHE 2 , activates IKK signaling, which may contribute to neoplastic transformation

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“…However, the catecholestrogens can also be oxidized to form reactive semiquinones and quinines, which can form adducts with purine bases (Dawling et al 2001, Belous et al 2007). COMT has a higher affinity for 2-OHE 2 over 4-OHE 2 , resulting in an increased genotoxicity of the 4-OHE 2 metabolite (Tsuchiya et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450-mediated 17β-estradiol metabolism in zebrafish (Danio rerio)

Scornaienchi

Thornton²,

Willett³

et al. 2010

Journal of Endocrinology

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Cytochrome P4501 (CYP1) and CYP3A proteins are primarily responsible for the metabolism of 17b-estradiol (E 2 ) in mammals. We have cloned and heterologously expressed CYP1A, CYP1B1, CYP1C1, CYP1C2, CYP1D1, and CYP3A65 from zebrafish (Danio rerio) to determine the CYP-mediated metabolism of E 2 in a non-mammalian species. Constructs of each CYP cDNA were created using a leader sequence from the bacterial ompA gene to allow appropriate expression in Escherichia coli without 5 0 modification of the gene. Membrane vesicles were purified, and functional CYP protein was verified using carbon monoxide difference spectra and fluorescent catalytic assays with the substrates 7-ethoxyresorufin and 7-benzyloxy-4-(trifluoromethyl)-coumarin. Rates of in vitro E 2 metabolism into 4-hydroxyE 2 (4-OHE 2 ), 2-hydroxyE 2 (2-OHE 2 ), and 16a-hydroxyE 1 (16a-OHE 1 ) metabolites were determined by gas chromatography/mass spectrometry. The 2-OHE 2 metabolite was produced by all CYPs tested, while 4-OHE 2 was only detected following incubation with CYP1A, CYP1B1, CYP1C1, and CYP1C2. The 16a-OHE 1 metabolite was only produced by CYP1A. The highest rates of E 2 metabolism were from CYP1A and CYP1C1, followed by CYP1C2. CYP1B1, CYP1D1, and CYP3A65 had low rates of E 2 metabolism. E 2 metabolism by zebrafish CYP1A, CYP1C1, and CYP1C2 produced similar ratios of 4-OHE 2 to 2-OHE 2 as previous studies with mammalian CYP1As. CYP1B1 formed the highest ratio of 4-OHE 2 to 2-OHE 2 metabolites. Contrary to mammals, these results suggest that fish CYP1A and CYP1C proteins are primarily responsible for E 2 metabolism, with only minor contributions from CYP3A65 and CYP1B1. Similar to mammals, 2-OHE 2 is the predominant metabolite from CYP-mediated E 2 metabolism in fish, suggesting that all vertebrate species produce the same major E 2 metabolite.

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Cytochrome P450 1B1–Mediated Estrogen Metabolism Results in Estrogen-Deoxyribonucleoside Adduct Formation

Cited by 78 publications

References 41 publications

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of IκB Kinase: Potential Role of Reactive Oxygen Species

Cytochrome P450-mediated 17β-estradiol metabolism in zebrafish (Danio rerio)

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