Involvement of genotoxic effects in the initiation of estrogen-induced cellular transformation: Studies using Syrian hamster embryo cells treated with 17?-estradiol and eight of its metabolites

Tsutsui, Takeki; Tamura, Yukiko; Yagi, Eiichi; Barrett, J. Carl

doi:10.1002/(sici)1097-0215(20000401)86:1<8::aid-ijc2>3.0.co;2-v

Cited by 49 publications

(38 citation statements)

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“…Two parent compounds of estrogen quinones, 4-OHE 1 and 4-OHE 2 , are mutagenic (inducing 5 ± 25610 76 oua-resistant and 3.3 ± 6.7610 76 hprt mutations, respectively, over a background of 1.2610 76 ) in Syrian hamster embryo (SHE) cells (Tsutsui et al, 2000). Since E 2 -3,4-Q forms primarily depurinating adducts, our results suggest that error-prone BER of abasic sites formed by E 2 -3,4-Q-induced depurination is a mutagenic mechanism.…”

Section: Discussionmentioning

confidence: 99%

Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene

et al. 2001

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Section: Discussionmentioning

confidence: 99%

Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene

et al. 2001

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“…6 Tsutsui et al 10 demonstrated that catechol estrogens have various genotoxic effects, such as chromosomal aberrations and gene mutations. Taken together with the previous and present results, it is concluded that in estrogen-induced carcinogenesis, estrogen metabolites, particularly catechol estrogens, are involved in the initiation process through oxidative DNA damage and estrogens themselves enhance cell proliferation, leading to tumor promotion and/or progression.…”

Section: Discussionmentioning

confidence: 99%

“…9 Catechol estrogens are also capable of causing chromosomal aberrations and gene mutations in cultured cells. 10 Thus, the genotoxic effects of estradiol could result from accumulation of potentially carcinogenic metabolites. Estradiol undergoes cytochrome P-450 -catalyzed hydroxylation to various catechol estrogens.…”

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Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation

et al. 2001

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Estrogen-induced carcinogenesis involves enhanced cell proliferation (promotion) and genotoxic effects (initiation).To investigate the contribution of estrogens and their metabolites to tumor initiation, we examined DNA damage induced by estradiol and its metabolites, the catechol estrogens 2-hydroxyestradiol (2-OHE 2 ) and 4-hydroxyestradiol (4-OHE 2 ). In the presence of Cu(II), catechol estrogens formed piperidine-labile sites at thymine and cytosine residues in 32 P 5 -end-labeled DNA fragments and induced the formation of 8-oxo-7, Epidemiological studies and animal experiments have revealed that estrogens are carcinogenic. 1 In humans, elevated circulating estrogen levels, caused either by increased endogenous hormone production or by therapeutic doses of estrogen medications, increase breast and uterine cancer risk. 2 Prolonged exposure of women to high estrogen levels is associated with an elevated incidence of breast cancer. 3 Administration of estradiol to mice increased the incidence of mammary, pituitary, uterine, cervical, vaginal, testicular, lymphoid and bone tumors. 2,4 In rats, estrogen increased the incidence of mammary and/or pituitary tumors. 2,5 Estrogens can cause cancer by stimulating cell proliferation and causing genotoxic damage. 6,7 Estrogens are highly mitogenic in hormone-sensitive tissues, such as the uterus and breast. 8 Prolonged exposure of target tissues and cells to excessive mitogenic stimulation by estrogens has been considered an important etiological factor for the induction of estrogen-associated cancers in experimental animals and humans. 8 Thus, estrogens are considered to participate in tumor promotion.However, estrogens have been reported to cause cancer through their genotoxic effects. Estradiol caused sister chromatid exchanges and chromosomal aberrations in peripheral blood human lymphocyte culture, and metabolic activation enhanced these chromosomal lesions. 9 Catechol estrogens are also capable of causing chromosomal aberrations and gene mutations in cultured cells. 10 Thus, the genotoxic effects of estradiol could result from accumulation of potentially carcinogenic metabolites. Estradiol undergoes cytochrome P-450 -catalyzed hydroxylation to various catechol estrogens. 8 2-Hydroxylation is a major metabolic pathway in the liver, whereas 4-hydroxylation dominates in extrahepatic organs susceptible to estrogens. 8,11,12 Catechol estrogens show much more potent carcinogenic effects on mice than estradiol. 13 Therefore, catechol estrogens can be potent carcinogens and may participate in tumor initiation by causing DNA damage.To investigate the role of catechol estrogens in tumor initiation, we examined DNA damage induced by 2-hydroxyestradiol (2-OHE 2 ) and 4-hydroxyestradiol (4-OHE 2 ) using 32 P 5Ј-end-labeled DNA fragments obtained from the human p53 tumor-suppressor gene and the c-Ha-ras-1 proto-oncogene. We also measured the formation of 8-oxo-7,8-dihydro-2Ј-deoxyguanosine (8-oxodG), an indicator of oxidative damage to DNA, using an electrochemical detector coup...

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“…2,3 Estrogen-induced genetic alterations are other possible mechanisms for estrogen-induced carcinogenesis. [3][4][5] Endogenous estrogens may be an etiological factor in the causation of certain types of human cancers, including breast, endometrium, ovary, prostate, and possibly, brain cancers. 6 The endogenous estrogens 17b-estradiol (E 2 ) and estrone (E 1 ) undergo oxidative metabolism, resulting in the production of 16a-hydroxyestrone and catechol estrogens [2-or 4-hydroxyestradiol (2-or 4-OHE 2 ) and 2-or 4-hydroxyestrone (2-or 4-OHE 1 )].…”

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confidence: 99%

“…3 These catechol estrogens also induce DNA adducts (detected by a 32 P-post-labeling) and chromosome aberrations in SHE cells, the abilities of which correspond well to the carcinogenic and transforming activities of the estrogens. 5,16 The results suggest that catechol estrogens of E 1 are more potent for the transforming and genotoxic activities than catechol estrogens of E 2 , and 4-hydroxy catechol estrogens are more potent than 2-hydroxy catechol estrogens. However, the mechanism of this difference remains undefined.…”

mentioning

confidence: 99%

Effects of a catechol‐O‐methyltransferase inhibitor on catechol estrogen‐induced cellular transformation, chromosome aberrations and apoptosis in Syrian hamster embryo cells

Hirose¹,

Tsutsui²,

Ohno³

et al. 2007

Intl Journal of Cancer

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To examine a possible mechanism of endogenous estrogen-induced carcinogenesis, we studied the effect of the catechol-O-methyltransferase (COMT) inhibitor Ro 41-0960 on cell transforming and clastogenic activities of 2 catechol estrogens 2-and 4-hydroxyestrone (2-or 4-OHE 1 ) using Syrian hamster embryo (SHE) cells. COMT activity was assayed by determining the methylation of 2-or 4-OHE 1 using gas chromatography. The production of 2-methoxyestrone in cultures treated with 2-OHE 1 was approximately 2-fold that of 4-methoxyestrone in cultures treated with 4-OHE 1 . 4-OHE 1 induced morphological transformation at a higher frequency than 2-OHE 1 did and the frequencies of cell transformation and chromosome aberrations were not significantly changed in cells treated with 4-OHE 1 in the presence of Ro 41-0960. In contrast, the frequencies of cell transformation and chromosome aberrations were markedly increased in cells treated with 2-OHE 1 along with Ro 41-0960 when compared to cells treated with 2-OHE 1 alone. In addition, both catechol estrogens induced P53 protein expression and apoptosis. The frequencies of apoptotic cells induced by the catechol estrogens were modified by the COMT inhibition in a manner similar to those observed with the chromosome aberrations assay and the cell transformation assay, indicating that each effect by the catechol estrogens at the three measured endpoints might be caused by a mechanism similar to the others. Our findings indicate that COMT activity has an influence on cell transforming activity and its related genetic effects of catechol estrogens in SHE cells, which implies that an individual activity of COMT may be one of the etiological factors in endogenous estrogen-induced carcinogenesis. ' 2007 Wiley-Liss, Inc.Key words: catechol estrogen; cellular transformation; chromosome aberrations; apoptosis; catechol-O-methyltransferase Estrogens are carcinogenic in humans and rodents, 1 but the mechanisms by which these hormones induce cancer are not fully elucidated. Accumulating evidence has suggested that epigenetic mechanisms of estrogens, related to stimulation of cell proliferation, mediated through the estrogen receptor are necessary, but not sufficient, to explain the carcinogenic activity of estrogens in vivo and in vitro under certain experimental conditions, because some estrogens are not carcinogenic.2,3 Estrogen-induced genetic alterations are other possible mechanisms for estrogen-induced carcinogenesis. [3][4][5] Endogenous estrogens may be an etiological factor in the causation of certain types of human cancers, including breast, endometrium, ovary, prostate, and possibly, brain cancers. 6 The endogenous estrogens 17b-estradiol (E 2 ) and estrone (E 1 ) undergo oxidative metabolism, resulting in the production of 16a-hydroxyestrone and catechol estrogens [2-or 4-hydroxyestradiol (2-or 4-OHE 2 ) and 2-or 4-hydroxyestrone (2-or 4-OHE 1 )]. 6 The catechol estrogens may be intermediates in estrogen-induced carcinogenesis. Administration of 4-OHE 1 or 4-OHE 2 at high nonphys...

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Involvement of genotoxic effects in the initiation of estrogen-induced cellular transformation: Studies using Syrian hamster embryo cells treated with 17?-estradiol and eight of its metabolites

Cited by 49 publications

References 12 publications

Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene

Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene

Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation

Effects of a catechol‐O‐methyltransferase inhibitor on catechol estrogen‐induced cellular transformation, chromosome aberrations and apoptosis in Syrian hamster embryo cells

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