Peroxidase-Dependent Metabolism of Benzene's Phenolic Metabolites and Its Potential Role in Benzene Toxicity and Carcinogenicity

Smith, Martyn T.; Yager, Janice W.; Steinmetz, Karen L.; Eastmond, David A.

doi:10.2307/3430757

Cited by 46 publications

(48 citation statements)

References 22 publications

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“…Together with David Eastmond and Richard Irons, I reported that phenol and hydroquinone, when administered together, produced bone marrow toxicity in mice that was very similar to that produced by benzene, whereas alone they did not (16). We postulated that peroxidase enzymes in the bone marrow, mainly myeloperoxidase (MPO), were responsible for the secondary activation of benzene's phenolic metabolites to toxic quinones and free radicals (17). Further, we showed that phenol would enhance the MPO-dependent oxidation of hydroquinone to 1,4-benzoquinone.…”

Section: A Role For Multiple Metabolitesmentioning

confidence: 99%

The Mechanism of Benzene-Induced Leukemia: A Hypothesis and Speculations on the Causes of Leukemia

Smith¹

1996

Environmental Health Perspectives

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104

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An overall hypothesis for benzene-induced leukemia is proposed. Key components of the hypothesis include a) activation of benzene in the liver to phenolic metabolites; b) transport of these metabolites to the bone marrow and conversion to semiquinone radicals and quinones via peroxidase enzymes; c) generation of active oxygen species via redox cycling; d) damage to tubulin, histone proteins, topoisomerase 11, other DNA associated proteins, and DNA itself; and e) consequent damage including DNA strand breakage, mitotic recombination, chromosome translocations, and aneuploidy. If these effects take place in stem or early progenitor cells a leukemic clone with selective advantage to grow may arise, as a result of protooncogene activation, gene fusion, and suppressor gene inactivation. Epigenetic effects of benzene metabolites on the bone marrow stroma, and perhaps the stem cell itself, may then foster development and survival of the leukemic clone. Evidence for this hypothesis is mounting with the recent demonstration that benzene induces gene-duplicating mutations in human bone marrow and chromosome-specific aneuploidy and translocations in peripheral blood cells. If this hypothesis is correct, it also potentially implicates phenolic and quinonoid compounds in the induction of "spontaneous" leukemia in man.

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Section: A Role For Multiple Metabolitesmentioning

confidence: 99%

The Mechanism of Benzene-Induced Leukemia: A Hypothesis and Speculations on the Causes of Leukemia

Smith¹

1996

Environmental Health Perspectives

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104

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“…Benzene oxide forms phenol spontaneously or conjugates with glutathione to form less toxic or nontoxic derivates via glutathione-S-transferases (GSTs). Phenol is catalyzed by CYP2E1 to potentially toxic di-or trihydroxybenzenes such as hydroquinone, catechol, and 1,2,4-benzentriol (Eastmond et al 1987;Smith et al 1989;Subrahmanyam et al 1991). The di-or trihydroxy metabolites are further oxidized in the bone marrow by myeloperoxidase (MPO) to benzoquinones (Schattenberg et al 1994), a potent hematotoxic and genotic agent, which can be detoxified by NAD(P)H:quinone oxidoreductase 1 (NQO1) to less harmful hydroxybenzenes (Joseph et al 2000;Ross et al 1996).…”

mentioning

confidence: 99%

Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning.

Wan

Shi²,

Hui³

et al. 2002

Environ Health Perspect

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Metabolic enzymes involved in benzene activation or detoxification, including NAD(P)H, quinone oxidoreductase 1 (NQO1), cytochrome P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase mu-1 (GSTM1), and glutathione-S-transferase theta-1 (GSTT1), were studied for their roles in human susceptibility to benzene poisoning. The potential interactions of these metabolic enzymes with lifestyle factors such as cigarette smoking and alcohol consumption were also explored. We studied 156 benzene-poisoning patients and 152 workers occupationally exposed to benzene in South China. Sequencing, denaturing HPLC, restriction fragment-length polymorphism, and polymerase chain reaction were used to detect polymorphisms on the promoters and complete coding regions of NQO1, CYP2E1, MPO, and the null genotypes of GSTM1 and GSTT1. Seventeen single nucleotide polymorphisms (SNPs) were identified in NQO1, CYP2E1, and MPO genes, including 6 novel SNPs in CYP2E1 and MPO. Of the subjects who smoked and drank alcohol, an 8.15-fold [95% confidence interval (CI), 1.43-46.50] and a 21.50-fold (95% CI, 2.79-165.79) increased risk of benzene poisoning, respectively, were observed among the subjects with two copies of NQO1 with a C-to-T substitution in cDNA at nucleotide 609 (c.609 C>T variation; i.e., NQO1 c.609 T/T) compared to those with the heterozygous or wild (NQO1 c.609 C/T and c.609 C/C) genotypes. Our data also indicated that individuals with CYP2E1 c.-1293 C/C and c.-1293 G/C, and NQO1 c.609 T/T, and GSTT1 null genotypes tended to be more susceptible to benzene toxicity. Our results suggest that the combined effect of polymorphisms in NQO1, CYP2E1, and GSTT1 genes and lifestyle factors might contribute to benzene poisoning.

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“…When the mice were given the same total dose of 2 mg/kg divided into three daily ip injections of 0.67 mg/kg MUC for 10 and 16 days, similar effects, but of much lesser magnitude, were observed. Bone marrow toxicity of MUC was also demonstrated by Snyder et al (24) using inhibition of incorporation of radioactive iron into cell hemoglobin as a toxic end point indicative of inhibitory effects on proliferation and differentiation of bone marrow erythroid cells (25). In their studies, dose-dependent decreases in 59Fe incorporation were observed in Swiss albino mice administered 1, 2, or 4 mg/kg MUC in an experimental regimen that involved three treatments per dose during a 24-hr period.…”

Section: Formation Of Ring-opened Metabolites Of Benzenementioning

confidence: 75%

Reactive Ring-Opened Aldehyde Metabolites in Benzene Hematotoxicity

Witz¹,

Zhang²,

Goldstein³

1996

Environmental Health Perspectives

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The aldehydic MUC metabolite 6-hydroxy-trans-trans-2,4-hexadienal (CHO-M-OH), similar to MUC but to a lesser extent, is reactive toward glutathione, mutagenic in V79 cells, and hematotoxic in mice. It is formed by monoreduction of MUC, a process that is reversible and could be of biological significance in benzene bone marrow toxicity. The MUC metabolite 6-hydroxy-trans-trans-2,4-hexadienoic (COOH-M-OH) is an end product of MUC metabolism in vitro. Our studies indicate that COOH-M-OH is a urinary metabolite of benzene in mice, a finding that provides further indirect evidence for the in vivo formation of MUC from benzene. Mechanistic studies showed the formation of cis-trans-muconaldehyde in addition to MUC from benzene incubated in a hydroxyl radical-generating Fenton system. These results suggest that the benzene ring is initially opened to cis,cis-muconaldehyde, an unstable isomer that rearranges to cis-trans-muconaldehyde, which further rearranges to trans-trans-muconaldehyde. The latter is not formed from benzene dihydrodiol by reactive oxygen species in a Fenton system that contains reactive oxygen species.

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Peroxidase-Dependent Metabolism of Benzene's Phenolic Metabolites and Its Potential Role in Benzene Toxicity and Carcinogenicity

Cited by 46 publications

References 22 publications

The Mechanism of Benzene-Induced Leukemia: A Hypothesis and Speculations on the Causes of Leukemia

The Mechanism of Benzene-Induced Leukemia: A Hypothesis and Speculations on the Causes of Leukemia

Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning.

Reactive Ring-Opened Aldehyde Metabolites in Benzene Hematotoxicity

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