Detection of DNA adducts in HL-60 cells treated with hydroquinone and <i>p</i>-benzoquinone by <sup>32</sup>P-postlabeling

Lévay, György; Pongracz, Krisztina; Bodell, William J.

doi:10.1093/carcin/12.7.1181

Cited by 94 publications

(74 citation statements)

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“…Previous studies have compared the DNA adduct formed in HL-60 cells treated with HQ with the DNA adducts formed by reaction of BQ with DNA and found that the DNA adducts formed in HL-60 cells did not correspond to the benzetheno-DNA adducts (17,34). In the present study we have found that the DNA adduct formed in vivo after benzene administration co-chromatograhed with N2-(4-hydroxyphenyl)-2'-deoxyguanosine-3'-phosphate.…”

Section: Resultscontrasting

confidence: 40%

“…Following treatment, the animals were anesthetized and blood and bone marrow were collected. The levels of DNA adducts in these tissues were investigated using P1-enhanced 32P-postlabeling (17)(18)(19)27). The presence of DNA adducts was very dependent upon the benzene treatment schedule.…”

Section: Dna Adduct Formation In Vivomentioning

confidence: 99%

“…Structural analysis and 32P-postlabeling of the isolated products allowed identification of the DNA adducts as (3'-hydroxy)-zetheno-2'-deoxycytidine-3'-(no. 2), (3'-hydroxy)-1,N6-be 2'-deoxyadenosine-3'-phospha and (3'-hydroxy)-1,N2-bei 2'-deoxyguanosine-3'-phosph; (17,28,29 …”

Section: Structure Of Dna Adduct Forned In Vivomentioning

confidence: 99%

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Investigation of the DNA Adducts Formed in B6C3F1 Mice Treated with Benzene: Implications for Molecular Dosimetry

Bodell¹,

Pathak²,

Lévay³

et al. 1996

Environmental Health Perspectives

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We have investigated the formation of DNA adducts in the bone marrow and white blood cells of male B6C3F1 mice treated with benzene using P1-enhanced 32P-postlabeling. No adducts were detected in the bone marrow of controls or mice treated with various doses of benzene once a day. After twice-daily treatment for 1 to 7 days with benzene, 440 mg/kg, one major (no. 1) and up to two minor DNA adducts were detected in both the bone marrow and white blood cells. The relative adduct levels in these cells ranged from 0.06 to 1.46 x 10-7. A significant correlation (r2 = 0.95) between levels of adducts in bone marrow and white blood cells was observed. After a 7-day treatment with benzene, 440 mg/kg twice a day, the number of cells per femur decreased from 1.6 x 107 to 0.85 x 107, indicating myelotoxicity. In contrast, administration of benzene once a day produced only a small decrease in bone marrow cellularity. The observed induction of toxicity in bone marrow was paralleled by formation of DNA adducts. In vitro treatment of bone marrow with hydroquinone (HQ) for 24 hr produced the same DNA adducts as found after treatment of mice with benzene, suggesting that HQ is the principal metabolite of benzene leading to DNA adduct formation in vivo. Using 32P-postlabeling the principal DNA adduct formed in vivo was compared with N2-(4-hydroxyphenyl)-2'-deoxyguanosine-3'-phosphate. The results of this comparison demonstrates that the DNA adduct formed in vivo co-chromatographs with N2-(4-hydroxyphenyl)-2'-deoxyguanosine-3'-phosphate. These studies indicate that metabolic activation of benzene leads to the formation of DNA adducts in bone marrow and white blood cells and suggest that measurement of DNA adducts in white blood cells may be an indicator of biological effect following benzene exposure.

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Section: Resultscontrasting

confidence: 40%

Section: Dna Adduct Formation In Vivomentioning

confidence: 99%

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Investigation of the DNA Adducts Formed in B6C3F1 Mice Treated with Benzene: Implications for Molecular Dosimetry

Bodell¹,

Pathak²,

Lévay³

et al. 1996

Environmental Health Perspectives

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“…Conversely, DMSO or retinoic acid induce their differentiation into polymorphonuclear cells. Recently, these myeloid cell lines have been utilized in toxicological studies (26)(27)(28). The data presented in Table 1 show that HL-60 cells have more GSH than ML-1 cells.…”

Section: Determinants Of Toxicity To Bone Marrow Cell Populationsmentioning

confidence: 99%

Analysis of target cell susceptibility as a basis for the development of a chemoprotective strategy against benzene-induced hematotoxicities.

Trush

Twerdok

Rembish

et al. 1996

Environ Health Perspect

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A goal of our research is to identify biochemical factors that underlie the susceptibility of bone marrow cell populations to benzene metabolites so as to develop a mechanistically based chemoprotective strategy that may be used in susceptible humans exposed to benzene. By doing biochemical risk analysis of bone marrow stromal cells from mice and rats and the human myeloid cell lines, HL-60 and ML-1; and by using buthionine sulfoximine and dicumarol we have observed that the susceptibility of these cell populations to hydroquinone (HQ) correlates with their concentration of glutathione (GSH) and activity of quinone reductase (QR). Accordingly, the induction of QR and GSH by 1,2-dithiole-3-thione (D3T) in these cell populations has resulted in a significant protection against the following hydroquinone-mediated toxicities: inhibition of cell proliferation and viability; reduced ability of stromal cells to support myelopoiesis; and altered differentiation of ML-1 cells to monocytes/macrophages. Preliminary in vivo experiments indicate that feeding mice D3T results in an induction of QR in the bone marrow compartment such that stromal cells are more resistant to hydroquinone-induced cytotoxicity in vitro. Overall, these studies suggest that in addition to hepatic cytochrome P4502E1, bone marrow OR and GSH are factors that could determine an individual's relative susceptibility to the toxic effects of benzene.

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“…Although the metabolites responsible for this binding have not been identified (20)(21)(22)(23), our 32p_ postlabeling studies have shown that HQ and p-benzoquinone (p-BQ) form the same DNA adduct in HL-60 promyelocytic leukemia cells (24). Neither phenol nor HQ is myelotoxic by itself, but in combination they have a myelotoxic effect similar to that ofbenzene (25).…”

mentioning

confidence: 98%

Potentiation of DNA adduct formation in HL-60 cells by combinations of benzene metabolites.

Lévay

Bodell

1992

Proc. Natl. Acad. Sci. U.S.A.

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Using P1 nuclease enhanced 32p postlabeling, we investigated DNA adduct formation in HL-60 promyelocytic leukemia cells treated with the benzene metabolites hydroquinone, catechol, and 1,2,4-benzenetriol. Comparison of the slopes of the dose-response curves showed that hydroquinone was 7-9 times more effective than 1,2,4,-benzenetriol and catechol at inducing DNA adducts. Comparison of hydroquinone with catechol showed a good correlation between adduct formation and cytotoxicity. Similar comparisons of hydroquinone and 1,2,4,-benzenetriol suggest that cellular processes in addition to DNA adduct formation contributed to cytotoxicity. In cells treated with the combination of hydroquinone and either catechol or 1,2,4,-benzenetriol, DNA adduct formation was 3-6 times greater than the sum of adduct formation produced by single-agent treatments. Treatment with hydroquinone and 1,2,4,-benzenetriol produced DNA adducts not detected after treatment with either metabolite alone. The synergistic interaction of benzene metabolites in the production of DNA adducts may play an important role in the genotoxic effects of benzene in vivo.Acute exposure to benzene has a strong toxic effect on the hematopoietic system of laboratory animals (1) and humans (2). Chronic exposure is carcinogenic in rats and mice (3, 4) and leukemogenic in humans (5, 6). To exert its toxic effects, benzene must be metabolized (7-9). The first step of benzene metabolism is the formation of benzene oxide by cytochrome P450 oxidation followed by either spontaneous conversion to phenol (9) or to 5,6-dihydroxy-1,3-cyclohexadiene by epoxide hydrolase. Phenol is further oxidized to hydroquinone (HQ). Catechol may be obtained by the rearomatization of 5,6-dihydroxy-1,3-cyclohexadiene by dihydrodiol dehydrogenase (10); 1,2,4-Benzenetriol (BT) results from the oxidation of either HQ or catechol. These metabolites accumulate in the bone marrow (7,11,12), where they may serve as reducing cosubstrates for peroxidases (12-16). The quinones or semiquinone radicals formed by peroxidase activation can react with both DNA (17-19) and protein (14-16).Benzene administration has resulted in the formation of DNA adducts in vivo. Although the metabolites responsible for this binding have not been identified (20-23), our 32p_ postlabeling studies have shown that HQ and p-benzoquinone (p-BQ) form the same DNA adduct in HL-60 promyelocytic leukemia cells (24). Neither phenol nor HQ is myelotoxic by itself, but in combination they have a myelotoxic effect similar to that ofbenzene (25). The administration of phenol with either HQ or catechol resulted in a synergistic inhibition of 59Fe uptake by erythroid bone marrow cells in mice (26). Similarly, phenol and HQ have a strong synergistic effect on micronucleus formation in Swiss mice (27) and in human lymphocytes (28). These results suggest that the genotoxic effects of benzene may be due to a synergistic interaction of its metabolites.In this study, we investigated DNA adduct formation and cytotoxicity in HL-60 cells tr...

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Detection of DNA adducts in HL-60 cells treated with hydroquinone and p-benzoquinone by ³²P-postlabeling

Cited by 94 publications

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Investigation of the DNA Adducts Formed in B6C3F1 Mice Treated with Benzene: Implications for Molecular Dosimetry

Investigation of the DNA Adducts Formed in B6C3F1 Mice Treated with Benzene: Implications for Molecular Dosimetry

Analysis of target cell susceptibility as a basis for the development of a chemoprotective strategy against benzene-induced hematotoxicities.

Potentiation of DNA adduct formation in HL-60 cells by combinations of benzene metabolites.

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Detection of DNA adducts in HL-60 cells treated with hydroquinone and p-benzoquinone by 32P-postlabeling

Cited by 94 publications

References 0 publications

Investigation of the DNA Adducts Formed in B6C3F1 Mice Treated with Benzene: Implications for Molecular Dosimetry

Investigation of the DNA Adducts Formed in B6C3F1 Mice Treated with Benzene: Implications for Molecular Dosimetry

Analysis of target cell susceptibility as a basis for the development of a chemoprotective strategy against benzene-induced hematotoxicities.

Potentiation of DNA adduct formation in HL-60 cells by combinations of benzene metabolites.

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Detection of DNA adducts in HL-60 cells treated with hydroquinone and p-benzoquinone by ³²P-postlabeling