A Study of Developmental Toxicity of Hydroquinone in the Rabbit

Murphy, S. J.; Schroeder, Raymond E.; Blacker, Ann M.; Krasavage, Walter J.; English, J. Caroline

doi:10.1093/toxsci/19.2.214

Cited by 7 publications

(9 citation statements)

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“…128 Developmental toxicity of HQ was investigated in female New Zealand White rabbits dose with 25, 75, or 150 mg/kg HQ, p.o., on gd 6 to 18. 331 Slightly decreased maternal body weights and food consumption were noted at the two higher dose levels. No statistically significant teratogenic alterations were observed in offspring from treated rabbits when compared with control.…”

Section: Reproductive and Developmental Effectsmentioning

confidence: 94%

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

173

125

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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: Reproductive and Developmental Effectsmentioning

confidence: 94%

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

173

125

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“…TG has become a very useful tool for experimental manipulations of Ca 2ϩ signaling in cells and is presently considered for possible therapeutic applications (Denmeade and Isaacs, 2005;Søhoel et al, 2006). After the discovery of the TG effect, other compounds, such as cyclopiazonic acid (CPA) (Goeger et al, 1988;Seidler et al, 1989), 2,5-di(tert-butyl)hydroquinone (DBHQ) (Moore et al, 1987;Murphy et al, 1992), and 1,3-dibromo-2,4,6-tri(methylisothiouronium)benzene (TITU) (Berman and Karlish, 2003;Hua et al, 2005), were found to inhibit SERCA (Fig. 1).…”

mentioning

confidence: 99%

Effects of High-Affinity Inhibitors on Partial Reactions, Charge Movements, and Conformational States of the Ca²⁺Transport ATPase (Sarco-Endoplasmic Reticulum Ca²⁺ATPase)

Tadini‐Buoninsegni

Bartolommei²,

Moncelli³

et al. 2008

Mol Pharmacol

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The inhibitory effects of thapsigargin, cyclopiazonic acid, and 2,5-di(tert-butyl)hydroquinone, and 1,3-dibromo-2,4,6-tri(methylisothiouronium)benzene on the Ca 2ϩ ATPase were characterized by comparative measurements of sequential reactions of the catalytic and transport cycle, including biochemical measurements and detection of charge movements within a single cycle. In addition, patterns of ATPase proteolytic digestion with proteinase K were derived to follow conformational changes through the cycle or after inhibitor binding. We find that thapsigargin, cyclopiazonic acid, and 2,5-di(tert-butyl)hydroquinone inhibit Ca 2ϩ binding and catalytic activation as demonstrated with isotopic tracers and lack of charge movement upon addition of Ca 2ϩ in the absence of ATP. It has been shown previously that binding of these inhibitors requires the E2 conformational state of the ATPase, obtained in the absence of Ca 2ϩ . We demonstrate here that E2 state conformational features are in fact induced by these inhibitors on the ATPase even in the presence of Ca 2ϩ . The resulting dead-end complex interferes with progress of the catalytic and transport cycle. Inhibition by 1,3-dibromo-2,4,6-tri(methylisothiouronium)benzene, on the other hand, is related to interference with a conformational transition of the phosphorylated intermediate (E1ϳP ⅐ 2Ca 2ϩ to E2-P ⅐ 2Ca 2ϩ transition), as demonstrated by increased phosphoenzyme levels and absence of bound Ca 2ϩ translocation upon addition of ATP. This transition includes large movements of ATPase headpiece domains and transmembrane segments, produced through utilization of ATP-free energy as the "conformational work" of the pump. We conclude that the mechanism of high-affinity Ca 2ϩ ATPase inhibitors is based on global effects on protein conformation that interfere with ATPase cycling.

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“…Hydroquinone is classified in the DART assessment along with the halogen-and nitro-substituted phenols, due to high structural resemblance. However, regarding its chemical reactivity, this classification appears questionable and there are studies showing that hydroquinone is indeed not a developmental toxicant in rats or rabbits [35][36][37].…”

Section: False Negativesmentioning

confidence: 99%

Prediction of embryotoxic potential using the ReProGlo stem cell-based Wnt reporter assay

Uibel¹,

Schwarz²

2015

Reproductive Toxicology

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A Study of Developmental Toxicity of Hydroquinone in the Rabbit

Cited by 7 publications

References 0 publications

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

Effects of High-Affinity Inhibitors on Partial Reactions, Charge Movements, and Conformational States of the Ca²⁺Transport ATPase (Sarco-Endoplasmic Reticulum Ca²⁺ATPase)

Prediction of embryotoxic potential using the ReProGlo stem cell-based Wnt reporter assay

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A Study of Developmental Toxicity of Hydroquinone in the Rabbit

Cited by 7 publications

References 0 publications

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

Effects of High-Affinity Inhibitors on Partial Reactions, Charge Movements, and Conformational States of the Ca2+Transport ATPase (Sarco-Endoplasmic Reticulum Ca2+ATPase)

Prediction of embryotoxic potential using the ReProGlo stem cell-based Wnt reporter assay

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Effects of High-Affinity Inhibitors on Partial Reactions, Charge Movements, and Conformational States of the Ca²⁺Transport ATPase (Sarco-Endoplasmic Reticulum Ca²⁺ATPase)