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.
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雌性 ACI 大鼠中抗氧化剂诱导 NAD(P)H-醌氧化还原酶 1 与减少氧化性 DNA 损伤和抑制雌激素诱导的乳腺癌有关。
DOI：
10.1093/carcin/bgr237
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发表时间：
2012
期刊：
影响因子：
4.7
通讯作者：
Bhat,HariK
中科院分区：
文献类型：
--
作者：
Singh,Bhupendra;Bhat,NimeeK;Bhat,HariK
雌激素相关癌症的发生和发展的确切机制尚不清楚。文献、证据和我们的研究强烈支持雌激素代谢介导的氧化应激在雌激素诱导的乳腺癌发生中的作用。我们最近已经证明，抗氧化剂维生素C和丁基羟基茴香醚（BHA）或雌激素代谢抑制剂α-萘酚酮（ANF）抑制17β-雌二醇（E2）诱导的雌性ACI大鼠乳腺肿瘤的发生。本研究的目的是确定抗氧化剂介导的保护机制对E2诱导的DNA损伤和乳腺肿瘤的发生。雌性ACI大鼠在维生素C或BHA或ANF存在或不存在的情况下用E2治疗长达240天。核因子红细胞2相关因子2（NRF 2）和NAD（P）H-醌氧化还原酶1（NQO 1）被抑制在E2暴露的乳腺组织和乳腺肿瘤后，大鼠与E2治疗240天。这种抑制被克服的共同治疗的大鼠与E2和维生素C或BHA。时间进程研究表明，NQO 1水平在E2治疗4个月后趋于增加，但在长期暴露于E2 8个月后下降。维生素C和BHA在120天后显著增加NQO 1水平。8-羟基脱氧鸟苷（8-OHdG）水平较高，在E2暴露的乳腺组织和乳腺肿瘤与年龄匹配的控制。维生素C或BHA处理显著降低了E2介导的乳腺组织中8-OHdG水平的升高。使用沉默RNA的体外研究证实了NQO 1在预防氧化性DNA损伤中的作用。我们的研究进一步表明，抗氧化剂上调NQO 1是通过NRF 2介导的。
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 vitrostudies using silencer RNA confirmed the role ofNQO1in prevention of oxidative DNA damage. Our studies further demonstrate that NQO1 upregulation by antioxidants is mediated through NRF2.
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