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

Lévay, György; Bodell, William J.

doi:10.1073/pnas.89.15.7105

Cited by 51 publications

(40 citation statements)

References 33 publications

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“…[31][32][33][34][35] In particular, growing evidence suggests that metabolites derived from hydroquinone, including 1,2,4-benzenetriol and particularly 1,4-benzoquinone, [36][37][38] are highly toxic. [10][11][12][13] However, other studies have shown synergistic eVects between combinations of hydroquinone and other metabolites including phenol and catechol. [39][40][41] Thus, although the latest evidence points to hydroquinone having a central role in benzene toxicity, a role for other metabolites cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

Rothman¹,

Bechtold²,

Yin³

et al. 1998

Occup Environ Med

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Objectives-Animal inhalation studies and theoretical models suggest that the pattern of formation of benzene metabolites changes as exposure to benzene increases. To determine if this occurs in humans, benzene metabolites in urine samples collected as part of a cross sectional study of occupationally exposed workers in Shanghai, China were measured. Methods-With organic vapour monitoring badges, 38 subjects were monitored during their full workshift for inhalation exposure to benzene. The benzene urinary metabolites phenol, catechol, hydroquinone, and muconic acid were measured with an isotope dilution gas chromatography mass spectroscopy assay and strongly correlated with concentrations of benzene air. For the subgroup of workers (n=27) with urinary phenol >50 ng/g creatinine (above which phenol is considered to be a specific indicator of exposure to benzene), concentrations of each of the four metabolites were calculated as a ratio of the sum of the concentrations of all four metabolites (total metabolites) and were compared in workers exposed to >25 ppm v < 25 ppm. Results-The median, 8 hour time weighted average exposure to benzene was 25 ppm. Relative to the lower exposed workers, the ratio of phenol and catechol to total metabolites increased by 6.0% (p=0.04) and 22.2% (p=0.007), respectively, in the more highly exposed workers. By contrast, the ratio of hydroquinone and muconic acid to total metabolites decreased by 18.8% (p=0.04) and 26.7% (p=0.006), respectively. Similar patterns were found when metabolite ratios were analysed as a function of internal benzene dose (defined as total urinary benzene metabolites), although catechol showed a more complex, quadratic relation with increasing dose. Conclusions-These results, which are consistent with previous animal studies, show that the relative production of benzene metabolites is a function of exposure level. If the toxic benzene metabolites are assumed to be derived from hydroquinone, ring opened products, or both, these results suggests that the risk for adverse health outcomes due to exposure to benzene may have a supralinear relation with external dose, and that linear extrapolation of the toxic eVects of benzene in highly exposed workers to lower levels of exposure may underestimate risk. (Occup Environ Med 1998;55:705-711)

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Section: Discussionmentioning

confidence: 99%

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

Rothman¹,

Bechtold²,

Yin³

et al. 1998

Occup Environ Med

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“…26,28,29 Further, combinations of the phenolic metabolites of benzene enhance DNA adduct formation. 30,31 It has therefore been suggested that all the phenolic metabolites of benzene play a role in benzene-induced toxicity, and that it is the combination that is most toxic. 24,32 Phenol and hydroquinone produce genetic damage of the type found in leukemia Quinones derived from phenol, catechol, hydroquinone and 1,2,4-benzenetriol cause various forms of genetic damage Leukemia including chromosome breakage and aneuploidy.…”

Section: Figurementioning

confidence: 99%

Hypothesis: Phenol and hydroquinone derived mainly from diet and gastrointestinal flora activity are causal factors in leukemia

et al. 2001

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High background levels of phenol and hydroquinone are present in the blood and urine of virtually all individuals, but vary widely. Phenol and hydroquinone have been strongly implicated in producing leukemia associated with benzene exposure, because they reproduce the hematotoxicity of benzene, cause DNA and chromosomal damage found in leukemia, inhibit topoisomerase II, and alter hematopoiesis and clonal selection. The widely varying background levels of phenol and hydroquinone in control individuals stem mainly from direct dietary ingestion, catabolism of tyrosine and other substrates by gut bacteria, ingestion of arbutin-containing foods, cigarette smoking, and the use of some over-the-counter medicines. We hypothesize that these background sources of phenol and hydroquinone and associated adducts play a causal role in producing some forms of de novo leukemia in the general population. This hypothesis is consistent with recent epidemiological findings associating leukemia with diets rich in meat and protein, the use of antibiotics (which change gastrointestinal flora make-up), lack of breastfeeding, and low activity of NAD(P)H quinone oxidoreductase which detoxifies quinones derived from phenol and hydroquinone and protects against benzene hematotoxicity. An attractive feature of our hypothesis is that it may explain why many people who have no known occupational exposures or significant smoking history develop leukemia. The hypothesis predicts that susceptibility to the disease would be related to diet, medicinal intake, genetics and gut-flora composition. The latter two of these are largely beyond our control, and thus dietary modification and reduced use of medicines that elevate phenol levels may be the best intervention strategies for lowering leukemia risk. Leukemia (2001) 15, 10-20.

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“…Pongracz et al (30,31) and Levay et al (32) subsequently combined these spectroscopic methods of structural analysis with the sen- (36) and that peroxidase activation of hydroquinone is required for adduct formation (37), no attempts were made to link adduct formation with any end point of toxicity other than cytotoxicity. We recently evaluated the significance of DNA adduct formation in toxicity by studying the effects of benzene metabolites on DNA adduct formation and retinoic acid-induced granulocytic differentiation in this model (38).…”

Section: Microsomal Metabolismmentioning

confidence: 99%

An Overview of Benzene Metabolism

Snyder¹,

Hedli²

1996

Environ Health Perspect

105

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Benzene toxicity involves both bone marrow depression and leukemogenesis caused by damage to multiple classes of hematopoietic cells and a variety of hematopoietic cell functions. Study of the relationship between the metabolism and toxicity of benzene indicates that several metabolites of benzene play significant roles in generating benzene toxicity. Benzene is metabolized, primarily in the liver, to a variety of hydroxylated and ring-opened products that are transported to the bone marrow where subsequent secondary metabolism occurs. Two potential mechanisms by which benzene metabolites may damage cellular macromolecules to induce toxicity include the covalent binding of reactive metabolites of benzene and the capacity of benzene metabolites to induce oxidative damage. Although the relative contributions of each of these mechanisms to toxicity remains unestablished, it is clear that different mechanisms contribute to the toxicities associated with different metabolites. As a corollary, it is unlikely that benzene toxicity can be described as the result of the interaction of a single metabolite with a single biological target. Continued investigation of the metabolism of benzene and its metabolites will allow us to determine the specific combination of metabolites as well as the biological target(s) involved in toxicity and will ultimately lead to our understanding of the relationship between the production of benzene metabolites and bone marrow toxicity.

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

Cited by 51 publications

References 33 publications

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

Hypothesis: Phenol and hydroquinone derived mainly from diet and gastrointestinal flora activity are causal factors in leukemia

An Overview of Benzene Metabolism

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