Formation of reactive metabolites from benzene

Snyder, Robert; Jowa, Lubow; Witz, Gisela; Kalf, George F.; Rushmore, Thomas H.

doi:10.1007/bf00296948

Cited by 49 publications

(40 citation statements)

References 6 publications

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“…Similarly, benzoquinone was the most potent inhibitor of DNA synthesis in mouse L5178Y cells followed by hydroquinone, benzenetriol, catechol, and phenol (216). In addition, DNA adducts were formed, isolated, and partially characterized from rat liver mitoplasts incubated with benzene (217).…”

Section: Genetic Toxicologymentioning

confidence: 99%

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Huff

Haseman

DeMarini

et al. 1989

Environ Health Perspect

113

107

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Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3FW mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previ. ous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals.For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3FW mice, and female B6C3FM mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity. In male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, malignant lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), Harderian gland adenomas, and squamous cell carcinomas of the preputial gland. In female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benign mixed tumors, carcinomas and careinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcin...

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Section: Genetic Toxicologymentioning

confidence: 99%

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Huff

Haseman

DeMarini

et al. 1989

Environ Health Perspect

113

107

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“…These metabolites accumulate in the bone marrow (7,11,12), where they may serve as reducing cosubstrates for peroxidases (12)(13)(14)(15)(16). The quinones or semiquinone radicals formed by peroxidase activation can react with both DNA (17)(18)(19) and protein (14)(15)(16).…”

mentioning

confidence: 99%

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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“…Activation of the tyrosine kinase group of oncogenes may playing a key role in the neoplastic transformation of cells (5,29,30). Benzene may affect the tyrosine kinase groups of oncogenes by causing chromosomal damage, and malignancy may arise as a result.…”

Section: Discussionmentioning

confidence: 99%

Cytogenetic findings on shoe workers exposed long-term to benzene.

Tunca

Egelí

1996

Environ Health Perspect

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Cytogenetic analysis of peripheral blood lymphocytes was performed to detect cytogenetical alterations in 58 shoe workers (57 male and 1 female) who had been exposed to particular mutagenic or carcinogenic agents and in 20 subjects selected from the general population as a control group. Frequencies of damaged cells, including gaps, breaks, and rearrangements (acentric fragment, deletion, translocations) were scored for both groups. The incidence of chromosomal aberrations (particularly chromatid gaps and breaks) in the study group was significantly higher than in the control group. No effects of smoking were observed and breaks alone were found to be influenced by alcohol consumption. No significant correlation was detected between the working period in the group exposed to benzene and frequency of chromosomal aberrations. Benzene content was determined to be between 0 and 28.5% in eight kinds of glues studied by fractional distillation. Hexane content ranged between 0 and 68.35% using the same method. This study indicated that the content of benzene and hexane in the glues are above normal limits. Environ Health Perspect 104(Suppl 6): 1313-1317 (1996)

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Formation of reactive metabolites from benzene

Cited by 49 publications

References 6 publications

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

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

Cytogenetic findings on shoe workers exposed long-term to benzene.

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