Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair

Kasai, Hiroshi; Crain, Pamela F.; Kuchino, Yoshiyuki; Nishimura, Susumu; Ootsuyama, Akira; Tazaki, Hiroshi

doi:10.1093/carcin/7.11.1849

Cited by 916 publications

(416 citation statements)

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“…The amount of 8-oxodG was measured by a modification of the method of Kasai et al 22 The reaction mixtures containing 100 M/base calf thymus DNA fragments, catechol estrogen (2-OHE 2 or 4-OHE 2 ) or estradiol, 100 M NADH and 20 M CuCl 2 in 4 mM sodium phosphate buffer (pH 7.8) containing 5 M DTPA were incubated for 2 hr at 37°C. After ethanol precipitation, DNA was digested to the nucleosides with nuclease P 1 and calf-intestine phosphatase and analyzed with an HPLC-ECD as described previously.…”

Section: Measurement Of 8-oxodg Formation By Catechol Estrogensmentioning

confidence: 99%

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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Section: Measurement Of 8-oxodg Formation By Catechol Estrogensmentioning

confidence: 99%

Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation

et al. 2001

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“…The formation of thymine glycol and thymidine glycol in vivo has been used as a possible assay for oxidative DNA damage [28,43]. Very recently, the formation of 8-hydroxydeoxyguanosine in DNA by oxygen radicals was reported [44][45][46][47][48][49].…”

Section: Oxidative Damage To Dna and Its Relationship To Cancer And Amentioning

confidence: 99%

Do mitochondrial DNA fragments promote cancer and aging?

Richter

1988

FEBS Letters

211

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Reactive oxygen species are important in carcinogenesis, diseases, and aging, probably through oxidative damage of DNA. Our understanding of this relationship at the molecular level is very sketchy. It has recently been found that in mitochondria oxidative DNA damage is particularly high and may not be repaired efficiently. I propose that oxidatively generated DNA fragments escape from mitochondria and become integrated into the nuclear genome. This may transform cells to a cancerous state. Time‐dependent nuclear accumulation of mitochondrial DNA fragments may progressively change the nuclear information content and thereby cause aging. This proposal can be tested experimentally.

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“…The same radicals are also the principal reactive species in the mutagenic and carcinogenic effects of ionizing radiations. Of more than 20 different modifications supposed to be formed in DNA by the action of hydroxyl radicals, 8-hydroxy-2'-deoxyguanosine (oh*dG) [4,5] has been reported to occur in the DNA of various organs of ageing rats [6], and is detected in rodent and human urine [7]. Furthermore, the presence of oh'dG has also been reported in rat liver nuclear and mitochondrial DNAs [S].…”

Section: Introductionmentioning

confidence: 99%

Reduction in the amount of 8‐hydroxy‐2'‐deoxyguanosine in the DNA of SV40‐transformed human fibroblasts as compared with normal cells in culture

et al. 1993

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Received 29 December 1992DNA damage due to oxidative free radicals is considered to be a major cause of ageing and age-related diseases including cancer. Of more than 20 modifications formed in DNA by the action of hydroxyl radicals, 8-hydroxy-2'-deoxyguanosine (oh*dG) is potentially highly mutagenic and is known to occur most frequently. Using HPLC combined with electrochemical (HPLCIEC) detection of oh*dG, fivefold higher levels of oh*dG are detected in the DNA of cultured normal human skin fibroblasts as compared with SV40-transformed human fibroblasts MRC-5V2. In comparison, the levels of oh'dG were similar in the growth medium of both types of cells. Applications of this method range from studies on the genomic stability and instability of normal and cancerous cells to the clinical and laboratory testing of toxic substances and drugs.

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Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair

Cited by 916 publications

References 0 publications

Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation

Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation

Do mitochondrial DNA fragments promote cancer and aging?

Reduction in the amount of 8‐hydroxy‐2'‐deoxyguanosine in the DNA of SV40‐transformed human fibroblasts as compared with normal cells in culture

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