Metabolism of Phenol and Hydroquinone to Reactive Products by Macrophage Peroxidase or Purified Prostaglandin H Synthase

Schlosser, Michael J.; Shurina, Robert D.; Kalf, George F.

doi:10.2307/3430780

Cited by 13 publications

(19 citation statements)

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“…This process has been proposed to result in an increased oxidative stress that may be significant for quinone toxicity, 79,80 although evidence is available that this process is slow at physiological pH. 81 Semiquinone radicals can also combine to regenerate HQ and BQ by means of disproportionation. Brunmark and Cadenas proposed 48 an alternative mechanism of redox cycling, in which P450-mediated oxidation of HQ accompanied by GSH addition would form benzenetriol-SG, a derivative more likely to participate in cycling than HQ itself.…”

Section: Macromolecular Binding and Redox Reactionsmentioning

confidence: 99%

“…Peroxidase-mediated binding of [ 14 C]-HQ to albumin was observed with mouse peritoneal macrophage lysates and with purified prostaglandin-H synthase in the presence of H 2 O 2 ; binding was inhibited by cysteine, suggesting the formation of thiol adducts. 81,83 Covalent adducts of HQ to protein sulfur nucleophiles were measured in tissues of rats after administration of HQ. 84 Total adducts were determined as well as individual bound forms of HQ in which the HQ nucleus was substituted with mono-, di-, tri-, or tetra-substituents.…”

Section: Macromolecular Binding and Redox Reactionsmentioning

confidence: 99%

“…Schlosser et al 81 incubated 14 C-labeled HQ with a mouse peritoneal macrophage lysate and observed an H 2 O 2 -dependent protein binding of HQ-derived radiolabel; binding was inhibited by cysteine and by the peroxidase inhibitor aminotriazole but not by hydroxyl radical scavengers. These workers also reported HQ-derived covalent binding to both protein and DNA with purified PHS in the presence of either arachidonic acid or H 2 O 2 , a reaction inhibited by indomethacin.…”

Section: Myelotoxicity and Immunotoxicitymentioning

confidence: 99%

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The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

178

128

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Hydroquinone (HQ) is a high-volume commodity chemical used as a reducing agent, antioxidant, polymerization inhibitor, and chemical intermediate. It is also used in over-the-counter (OTC) drugs as an ingredient in skin lighteners and is a natural ingredient in many plant-derived products, including vegetables, fruits, grains, coffee, tea, beer, and wine. While there are few reports of adverse health effects associated with the production and use of HQ, a great deal of research has been conducted with HQ because it is a metabolite of benzene. Physicochemical differences between HQ and benzene play a significant role in altering the pharmacokinetics of directly administered when compared with benzene-derived HQ. HQ is only weakly positive in in vivo chromosomal assays when expected human exposure routes are used. Chromosomal effects are increased significantly when parenteral or in vitro assays are used. In cancer bioassays, HQ has reproducibly produced renal adenomas in male F344 rats. The mechanism of tumorigenesis is unclear but probably involves a species-, strain-, and sex-specific interaction between renal tubule toxicity and an interaction with the chronic progressive nephropathy that is characteristic of aged male rats. Mouse liver tumors (adenomas) and mononuclear cell leukemia (female F344 rat) have also been reported following HQ exposure, but their significance is uncertain. Various tumor initiation/promotion assays with HQ have shown generally negative results. Epidemiological studies with HQ have demonstrated lower death rates and reduced cancer rates in production workers when compared with both general and employed referent populations. Parenteral administration of HQ is associated with changes in several hematopoietic and immunologic endpoints. This toxicity is more severe when combined with parenteral administration of phenol. It is likely that oxidation of HQ within the bone marrow compartment to the semiquinone or p-benzoquinone (BQ), followed by covalent macromolecular binding, is critical to these effects. Bone marrow and hematologic effects are generally not characteristic of HQ exposures in animal studies employing routes of exposure other than parenteral. Myelotoxicity is also not associated with human exposure to HQ. These differences are likely due to significant route-dependent toxicokinetic factors. Fetotoxicity (growth retardation) accompanies repeated administration of HQ at maternally toxic dose levels in animal studies. HQ exposure has not been associated with other reproductive and developmental effects using current USEPA test guidelines. The skin pigment lightening properties of HQ appear to be due to inhibition of melanocyte tyrosinase. Adverse effects associated with OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, although higher incidences of this syndrome have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations. The most serious human health effect related to HQ is p...

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Section: Macromolecular Binding and Redox Reactionsmentioning

confidence: 99%

Section: Macromolecular Binding and Redox Reactionsmentioning

confidence: 99%

Section: Myelotoxicity and Immunotoxicitymentioning

confidence: 99%

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The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

178

128

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“…Purified prostaglandin H synthase has been shown to oxidize both phenol and hydroquinone to species that bind irreversibly to protein and DNA (46).…”

Section: Arachidonic Acid-dependent Activation Of Phenol By Macrophagesmentioning

confidence: 99%

Prevention of benzene-induced myelotoxicity by nonsteroidal anti-inflammatory drugs.

Kalf

Schlosser

Renz

et al. 1989

Environ Health Perspect

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Benzene affects hematopoietic progenitor cells leading to bone marrow depression and genotoxic effects such as micronucleus fonnation. Progenitor cell proliferation and differentiation are inhibited by prostaglandins produced by macrophages. Administration of benzene to DBA/2 or C57BL/6 mice caused a dose-dependent bone marrow depression and a significant increase in marrow prostaglandin E level and both were prevented by the coadministration of indomethacin and other inhibitors of the cyclooxygenase component of prostaglandin H synthase. Levels of benzene that decreased bone marrow cellularity also caused genotoxic effects measured as increased micronucleated polychromatic erythrocytes in peripheral blood, which was also prevented by the coadministration of indomethacin. These results suggest a possible role for prostaglandin synthase in benzene myelotoxicity; a mechanism by which this might occur is presented.

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“…To date, studies on benzene have focused on its metabolic pathways to determine the metabolites responsible for its hematotoxicity and leukemogenicity (Henderson 1996;Schlosser et al 1989;Schrenk et al 1996;Snyder and Hedli 1996). Benzene and its major metabolites are not mutagenic in the Ames Salmonella test (Dean 1985), but they do induce chromosomal aberration both in vitro and in vivo (Dean 1985;Wolman 1977;Yager et al 1990).…”

mentioning

confidence: 99%

Mechanisms of Benzene-Induced Hematotoxicity and Leukemogenicity: cDNA Microarray Analyses Using Mouse Bone Marrow Tissue

Yoon¹,

Li²,

Kitada³

et al. 2003

Environ. Health Perspect.

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Although the mechanisms underlying benzene-induced toxicity and leukemogenicity are not yet fully understood, they are likely to be complicated by various pathways, including those of metabolism, growth factor regulation, oxidative stress, DNA damage, cell cycle regulation, and programmed cell death. With this as a background, we performed cDNA microarray analyses on mouse bone marrow tissue during and after a 2-week benzene exposure by inhalation. Our goal was to clarify the mechanisms underlying the hematotoxicity and leukemogenicity induced by benzene at the level of altered multigene expression. Because a few researchers have postulated that the cell cycle regulation mediated by p53 is a critical event for benzene-induced hematotoxicity, the present study was carried out using p53-knockout (KO) mice and C57BL/6 mice. On the basis of the results of large-scale gene expression studies, we conclude the following: a) Benzene induces DNA damage in cells at any phase of the cell cycle through myeloperoxidase and in the redox cycle, resulting in p53 expression through Raf-1 and cyclin D-interacting myb-like protein 1. b) For G1/S cell cycle arrest, the p53-mediated pathway through p21 is involved, as well as the pRb gene-mediated pathway. c) Alteration of cyclin G1 and Wee-1 kinase genes may be related to the G2/M arrest induced by benzene exposure. d) DNA repair genes such as Rad50 and Rad51 are markedly downregulated in p53-KO mice. e) p53-mediated caspase 11 activation, aside from p53-mediated Bax gene induction, may be an important pathway for cellular apoptosis after benzene exposure. Our results strongly suggest that the dysfunction of the p53 gene, possibly caused by strong and repeated genetic and epigenetic effects of benzene on candidate leukemia cells, may induce fatal problems such as those of cell cycle checkpoint, apoptosis, and the DNA repair system, finally resulting in hemopoietic malignancies. Our cDNA microarray data provide valuable information for future investigations of the mechanisms underlying the toxicity and leukemogenicity of benzene.

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Metabolism of Phenol and Hydroquinone to Reactive Products by Macrophage Peroxidase or Purified Prostaglandin H Synthase

Cited by 13 publications

References 4 publications

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

Prevention of benzene-induced myelotoxicity by nonsteroidal anti-inflammatory drugs.

Mechanisms of Benzene-Induced Hematotoxicity and Leukemogenicity: cDNA Microarray Analyses Using Mouse Bone Marrow Tissue

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